key: cord-0008632-4t63660y
authors: Fazakerley, John K.; Buchmeiert, Michael J.
title: Pathogenesis of Virus-Induced Demyelination
date: 2008-03-01
journal: Adv Virus Res
DOI: 10.1016/s0065-3527(08)60087-1
sha: 7ac70544937971da0d91ef466686e9dc3fdd461b
doc_id: 8632
cord_uid: 4t63660y

Demyelination is a component of several viral diseases of humans. The best known of these are subacute sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML). There are a number of naturally occurring virus infections of animals that involve demyelination and many of these serve as instructive models for human demyelinating diseases. In addition to the naturally occurring diseases, many viruses have been shown to be capable of producing demyelination in experimental situations. In discussing virus-associated demyelinating disease, the chapter reviews the architecture and functional organization of the CNS and considers what is known of the interaction of viruses with CNS cells. It also discusses the immunology of the CNS that differs in several important aspects from that of the rest of the body. Experimental models of viral-induced demyelination have also been considered. Viruses capable of producing demyelinating disease have no common taxonomic features; they include both DNA and RNA viruses, enveloped and nonenveloped viruses. The chapter attempts to summarize the important factors influencing viral demyelination, their common features, and possible mechanisms.

Demyelination is the loss of myelin, the lipid sheath surrounding the neuronal axon. Myelin loss can occur following direct damage of the myelin (primary demyelination) or secondary to neuronal damage and axonal loss (secondary demyelination). Myelin is produced by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). The biochemistry of these two forms is different.

Demyelination is a component of several viral diseases of humans. The best known of these are subacute sclerosing panencephalitis (SSPE) of children, produced by measles virus, and progressive multifocal leukoencephalopathy (PML), produced in adults and children by J C papovavirus. Both are rare conditions, SSPE being a late onset complication of measles and PML occurring in association with immunosuppression. In addition to these two well-described examples of viral demyelination there are several other demyelinating diseases of possible viral etiology. These include the best known of human demyelinating diseases: multiple sclerosis (MS), for which circumstantial evidence has suggested an infectious etiology (reviewed by Acheson, 1972; Nathanson and Miller, 1978) , and Guillain-Barr6 syndrome, which has been described following both viral infection and immunization (Johnson, 1983; Schonberger et al., 1979) .

In the last few years it has become apparent that one of the major manifestations of acquired immunodeficiency syndrome (AIDS) is neurological disease. In addition to AIDS-related dementia, lesions of demyelination in the CNS have been described (reviewed by Johnson et al., 19881 , as has peripheral neuropathy (Lipkin et al., 1985; Cornblath et al., 1987) . The cause of the CNS demyelination remains speculative, and may be complex because immunosuppression in these patients allows numerous secondary infections and reactivation of latent viruses. A clear role is evolving for a related virus, human T leukemia virus type I (HTLV-I), which has been associated with tropical spastic paraparesis in the Caribbean and myelopathy in Japan (Gessain et al., 1985; Osame et al., 1986) . Both diseases involve CNS demyelination and are clinically similar to MS. Indeed, it has been suggested that a virus closely related to HTLV-I is the causative agent in MS (Koprowski et al., 1985) .

Encephalomyelitis with demyelination has been described following several well-known virus infections, including measles, vaccinia, smallpox, mumps, rubella, influenza, herpes, and Epstein-Barr infections (Miller et al., 1956; DeVries, 1960; Marsden and Hurst, 1932; Hart and Earle, 1975; Hoult and Flewett, 1960; Gudnadottir et al., 1964; Grose et al., 1975) . Postvaccinal encephalomyelitis with demyelination was first seen in the last century with the use of Pasteur's attenuated rabies vaccine. This was prepared from animal neural tissue and resulted in direct sensitization to CNS components. The eponymous vaccine virus, vaccinia, although successfully used t o eradicate smallpox, was also associated with numerous cases of demyelinating encephalomyelitis (Miller, 1953; DeVries, 1960) .

In addition to the well-known viruses detailed above, there are many viruses localized to discrete geographic regions that produce neurological disease in humans. These viruses are endemic and occasionally epidemic in tropical regions, and whereas the viral etiology is known, the neuropathology often remains undescribed. It is possible that demyelination is a component of many of these infections. There are also a number of other variously described, idiopathic human demyelinating conditions such as polyneuritis, optic neuritis, and transverse myelitis of unknown etiology.

There are a number of natural1:y occurring virus infections of animals that involve demyelination, and many of these serve as instructive models for human demyelinating diseases. These include visna in sheep, caprine encephalitis-arthritis in goats, canine distemper of dogs, a paramyxovirus of cats, and Marek's disease of fowl. In addition to the naturally occurring diseases, many viruses have been shown to be capable of producing demyelination in experimental situations. Some of these viruses are not neuroinvasive and must be inoculated intracerebrally; others are neuroinvasive variants or mutants of naturally occurring viruses. Viruses associated with natural and experimental demyelinating diseases are listed in Table I. To discuss virus-associated demyelinating disease it is first necessary to review the architecture and functional organization of the CNS. It is also necessary to consider what is known of the interaction of viruses with CNS cells. Much of our knowledge here comes from studies of nondempelinating neurotropic viruses. It is also necessary to understand the immunology of the CNS, which differs in several important aspects from that of the rest of the body. Much that is known of the immunology of the CIW has been learned from studies of experimental allergic encephalomyelitis (EAE), a CNS inflammatory disease induced by extraneural injection of myelin antigens. The relevant aspects of each of these areas will be considered in turn before considering experimental models of viral-induced demyelination. As will be seen, viruses capable of producing demyelinating disease have no common taxonomic features; they include both DNA and RNA viruses, enveloped and nonenveloped viruses. This is followed by an forming cells in the PNS are Schwann cells, the myelin is biochemically different, and astrocytes, oligodendrocytes and microglial cells are absent in the PNS.

Central nervous system neurons are morphologically and functionally diverse. All neurons produce neurofilament protein, neuronspecific enolase, and stain with silver. Much effort has been invested to differentiate subpopulations of neurons based on their neurotransmitter systems (reviewed by Gombos and Aunis, 1982) . It is likely that many viruses infect specific subpopulations of neurons; indeed, this has been shown to be the case for a few viruses. Lymphocytic choriomeningitis virus (LCMV) persists in somatostatin but not cholecystokinin-producing neurons (Lipkin et al., 1988) . Poliovirus infects predominantly motor neurons in the spinal cord and brainstem (Bodian, 1949) . Rabies virus preferentially infects pyramidal cells of the hippocampus and Purkinje cells of the cerebellum (Johnson, 1965; Murphy, 1977) . Variants of reovirus specifically localize to hippocampal and other neurons of the limbic system (Spriggs et al., 1983) . For many viruses the neuron is an ideal target cell. Neurons are metabolically active but nondividing, long-lived, and communicate directly and distantly throughout the body with many other neuronal and nonneuronal cells. Viral infections of neurons include acute, latent, and persistent infections; see Table 11 .

Astrocytes have been divided into two groups based on their reactivity with the antibody A2B5 (Raff et al., 1983a,b) . The intermediate filaments of astrocytes contain glial fibrillary acid protein (GFAP) and this is used as a characteristic marker of these cells (reviewed by Eng, 1982) . Astrocytes are found around the cerebral blood vessels, where their "foot processes" make contact with the basal surfaces of endothelial cells. The functions of astrocytes are not completely understood, but they are known to respond (astrocytic hypertrophy) to CNS injury (Bignami and Dahl, 1976) . Probable functions include a role in supplying the metabolic requirements of neurons, regulation of neurotransmitter production by neurons (Kimelberg and Norenberg, 1989) , and response to hormones and control of immune responses in the CNS (see Section 1,D). Viruses that infect astrocytes in uiuo include visna virus, canine distemper virus, herpes simplex, JC papovavirus, and mouse hepatitis virus (see Table 11 ).

Oligodendrocytes are the cells of the CNS that form the myelin sheath that surrounds axons. They are found throughout the CNS, but predominate in the white matter, where chains of oligodendrocytes are a characteristic feature. For a review on the biology of oligodendrocytes see Bartlett and Mackay (1983) and Bologna (1985) . The cell lineage relationships of CNS cells have been the subject of much research. Oligodendrocytes and type 2 astrocytes appear to be derived from a common precursor cell (02A) which carries a marker recognized by the A2B5 and 0 4 antibodies (Raff et al., 1983b; Trotter and Schachner, 1989) . Maturation of this bipotential progenitor cell is under the control of platelet-derived growth factor produced by type 1 astrocytes (Raff et al., 1988) . The 0 series of monoclonal antibodies, 04, 01, and 010, define increasingly more mature stages of oligodendrocyte differentiation (Sommer and Schachner, 1981; Schachner, 1982) . Evidence also exists from neurogenesis studies in the cerebral cortex for a common precursor cell for neurons and oligodendrocytes (B. P. Williams et al., 1991) . The markers galactocerebroside and sulfatide are both expressed on the cell surface of oligodendrocytes a few J O H N K. FAZAKERLEY AND MICHAEL J. BUCHMEIER days prior to myelination (Abney et al., 1981) . Other surface markers include myelin basic protein (MBP) and sialosylgalactosyl cerebroside GM4 (Yu and Iqbal, 1979) . Oligodendrocytes and astrocytes also produce the enzymes carbonate dehydratase and 2',3'-cyclic-nucleotide 3'phosphodiesterase, the latter a marker of oligodendrocyte differentiation (for reviews on marker enzymes of glial cells, see Schousboe, 1982; Giacobini, 1987) . Oligodendrocytes vary in size and support different numbers of internodes; small cells probably myelinate internodes on several small-diameter axons, while large cells may myelinate a single or a few internodes on large-diameter axons (Bunge, 1968; 1982) . The fact that one oligodendrocyte can myelinate many axonal internodes is an important consideration in CNS demyelinating disease, because destruction of a single oligodendrocyte can result in the demyelination of many internodes. In contrast, the loss of one Schwann cell in the peripheral nervous system results in demyelination of a single internode. Under normal conditions oligodendrocytes are long-lived, nonproliferating cells, with a large turnover of cellular membranes. Like neurons, oligodendrocytes are targets for several viral infections; see Table 11 . Oligodendrocytes produce myeliri by wrapping and compacting specialized extensions of their plasma membrane in concentric multiple lamina around the axon. The major protein components of myelin are proteolipid protein (PLP), myelin-associated glycoprotein (MAG), myelin basic protein (MBP), and glycolipids such as galactocerebroside. The myelin protein genes have now been cloned and sequenced. The MBP gene in the mouse has at least five differentially spliced forms (de Ferra et al., 1985 ; Newman e t a / . , 1987). The rat MAG gene has two differentially spliced forms, one of which is expressed in myelinating, suckling rats, the other in fully myelinated adult rats (C. Lai et al., 1987) . Each MAG message produces a distinct size of protein. The signals that control and regulate the differential splicing of these myelin genes are not clear. Further studies may lead to an understanding of developmentally regulated events in primary myelination and in myelin repair following demyelination.

Of the major cell types in the CNS probably the least in known about microglial cells. During development in the rat, two types of microglia can be recognized: ameboid microglia (brain macrophages) which differentiate into ramified microglia, characteristic of the adult brain. This differentiation, at least in vitro, appears to be regulated by the relative levels of the extracellular matrix proteins laminin and fibronectin (Chamak and Mallat, 1991) . In the resting adult rat brain, microglia have also been divided into two populations, the ramified microglia situated within the CNS parenchyma and the perivascular (adventitial or perithelial) microglia situated around small blood vessels (Mato et al., 1985) . Studies on bone marrow chimeras indicate that at least the perivascular microglia are bone marrow derived (Hickey and Kimura, 1988) . Following damage t o the CNS at sites of neuronal destruction or inflammation, ameboid brain macrophages reappear. These cells are derived from the resident microglia (Graeber et al., 19891, are phagocytic (Streit and Kreutzberg, 19881 , produce cytokines that can stimulate astrocytes and neurons, express macrophage monocyte markers (Graeber et al., 19901 , and are involved in the initiation of immune responses (see Section 1,D).

Cerebral endothelial cells differ from those of other tissues by their tight junctions, low levels of cytoplasmic vesicles, presence of transferrin receptors, and absence (in the rat) of the OX43 antigen that is present on other endothelial cells (Jefferies et al., 1984; Robinson et al., 1986) . At the anatomical level, the barrier between the blood and the brain is formed by the tight junctions between the endothelial cells of the cerebral capillaries and the cells of the arachnoid meninges and choroid plexus. The cerebrospinal fluid (CSF) is generated mostly at the choroid plexi by selective filtration. Selectivity is high because total protein in the CSF is about 0.4% the level in serum. No organized lymphatic tissue is demonstrable within the CNS, although it has been suggested that the CSF drains to the deep cervical lymph nodes via a lymphatic channel possibly arising in the region of the carotid foramen (Bradbury and Cole, 1980 (Brightman, 1968) . This seems to be the case with the alphaviruses Semliki Forest virus, and eastern equine encephalitis virus (Pathak and Webb, 1980; Murphy and Whitfield, 19701 , and is probably the most common route of CNS infection. Viruses may also cross the blood-brain barrier within normally recirculating or inflammatory mononuclear cells, as has been suggested for canine distemper virus, cytomegalovirus, and human immunodeficiency virus (HIV) (Summers et al., 1978; Wiley and Nelson, 1989) .

The tight junctions of the cerebral endothelial cells, the low level of CSF immunoglobulins (1/500 serum), the absence of lymphatic organization, low to undetectable levels of major histocompatibility (MHC) molecules, and the failure t o detect lymphocytes in the CNS have all contributed to the long-held concept that this organ is an immunologically privileged site. However, recent research indicates that this view is open to reinterpretation. Intravenous transfer of isotopically labeled T cell clones to naive, syngeneic rats has demonstrated that cloned, activated T cells can normally cross the blood-brain barrier but that only cells that encounter antigen remain localized to initiate an inflammatory response (Wekerle et al., 1987; Cross et al., 1990) .

The precise sequence of events that occur in the initiation, expansion, and specific localization of CNS immune responses remains unclear. Recognition of antigens in association with MHC molecules is required in both the inductive and effector phases of the immune response. This recognition places constraints on responses against CNS pathogens because cells of the CNS express low or undetectable levels of MHC molecules in the resting state. It has become clear, however, that various signals can enhance constitutive low levels of MHC class I expression and induce MHC class I1 expression on CNS cells.

At the interface between the brain and circulating lymphocytes are the cerebral endothelial cells. Presentation of viral antigens by MHC molecules displayed on the luminal surface of endothelial cells could be important in recruiting T cells into the CNS at the sites of infection.

In culture, MHC class I expression can be enhanced, and MHC class I1 induced, on these cells by treatment with interferon y (Male et al., 1987) . This effect can in turn be modulated by infection with virus (see Section 11,A). There is some debate as to whether endothelial cells can function as efficient antigen-presenting cells (McCarron et al., 1985; Pryce et al., 1989) . In uiuo, the inducibility of class I1 on cerebral endothelial cells is controversial. Some studies of inflammatory disease find these cells express MHC class I1 (Traugott and Raine, 1985; Sobel et al., 19841 , others find them negative Vass et al., 1986) . In uiuo, cerebral endothelial cells constitutively express a high-affinity form of LFA-1 (Dustin and Springer, 1989) . Morphological changes in cerebral endothelial cells have been observed at sites of CNS inflammation (Cross et al., 1990) , as has expression of a marker of high endothelial venules recognized by the antibody MECA-325 (Cannella et a1 ., 1990) . In chronic relapsing experimental allergic encephalomyelitis (see Section I,E), which is characterized by episodes of CNS inflammation, increased expression of MHC class 11, ICAM-1, and MECA-325 on cerebral vessels correlates with influx of inflammatory cells (Sakai et al., 1986; Cannella et al., 1990) .

A role seems to be emerging for perivascular microglial cells as important antigen-presenting cells in the initiation of CNS inflammatory reactions (Hinrichs et al., 1987; Hickey and Kimura, 1988; Cross et al., 1991) . Perivascular microglia and, at sites of injury or inflammation, parenchymal microglia (see Section I,C), have been observed to express several macrophage and monocyte markers, including MHC class I and 11, CD4,0X42 (CR31, ED1, ED3, and low levels of CD45 Hickey and Kimura, 1988; Graeber et al., 1990; Sedgwick et al., 1991) . These cells can also secrete interleukins (Woodroofe et al., 1991) . Perivascular microglia constitutively express MHC class I1 (Perry and Gordon, 1988; Mattiace et al., 19901 , can function as antigen-presenting cells for the induction of experimental allergic encephalomyelitis (EAE) (Hickey and Kimura, 1988) , and have been suggested to be the key cell in the initiation of CNS immune responses (Cross et al., 1991) .

Closely associated with endothelial cells and the surrounding perivascular microglia are extensions of astrocytes known as astrocytic foot processes. Astrocytes also appear to have an important role in regulating CNS immune responses. Both type I and type I1 astrocytes (see Section I,C), have been shown in uitro and in uzuo to increase expression of MHC class I and to express MHC class I1 in response to interferon y (Hirsch et al., 1983; Wong et al., 1984; Male et al., 1987; Calder et al., 19881, and in uitro to function as antigen-presenting cells for the presentation of MBP to T cell lines (Fontana et al., 1984a) . Interferon y can also induce the expression of ICAM-1 on cultured human astrocytes and interferon p has been found to inhibit interferon y-induced expression of class I1 MHC at the transcriptional level (Ransohoff et al., 1991) . Astrocytes and gliomas in culture produce the cytokines interleukins 1 and 3 (IL-1, IL-31, and IL-1 production has been demonstrated in the brains of mice treated with endotoxin (Fontana et al., 1982 (Fontana et al., , 1983 (Fontana et al., , 1984b Frei et al., 1986) . These findings have led to the suggestion that astrocytes and endothelial cells mediate immune responses in the CNS by functioning as antigen-presenting cells and form an immune control system in the brain (Fontana and Fierz, 1985) ; this suggestion must now be modified t o include a role for microglial cells.

Induction of Ia molecules on cultured astrocytes by interferon is strain dependent in both rats and mice. Astrocytes from Lewis rats express much higher levels of Ia in response to interferon than astrocytes from BN rats (Massa et al., 1987a) . Similarly, SJL and BALB/c mice are high and low responders, respectively. These findings correlate with the severity of EAE seen in these animals. Lewis rats and SJL mice are highly susceptible to EAE, and BN rats and BALB/c mice are resistant to EAE (Wege et al., 1986) . Mouse strains (BIO.S and BlO.ASR2) susceptible to CNS demyelination following Theiler's virus infection also express Ia on astrocytes, oligodendrocytes, and endothelial cells in the spinal cord (Rodriguez et al., 1987a) but no expression was observed in mice (BlO.S[SRI) resistant to the disease.

There is also evidence for direct viral induction of MHC molecules on cultured astrocytes. Expression of fa molecules is induced on rat astrocytes by the binding of live or inactivated mouse hepatitis virus JHM (Massa et al., 19861 , and both class I and class I1 MHC molecules are induced by live or inactivated measles virus (Massa et al., 198713) . Levels of Ia expression on astrocytes are amplified by addition of tumor necrosis factor (TNF) (Massa et al., 1987b1 , a cytokine whose release is stimulated by virus infection (Wong and Goeddel, 1986) . In contrast, mouse astrocytes infected with mouse hepatitis virus (strain A591 express class I but not class I1 MHC and a soluble factor released by the astrocytes induces class I expression on oligodendrocytes (Suzumura et al., 1986 (Suzumura et al., , 1988 .

Neurons and oligodendrocytes differ from endothelial cells, astrocytes, and microglia in their expression of MHC molecules. In uitro, neither cell type constitutively expresses MHC class I or class 11. Class I but not class I1 molecules are inducible on both cells by treatment with interferon y (Hirsch et al., 1983; Wong et al., 1984; Suzumura et al., 1986; Calder et al., 1988; Joly et al., 1991) . In uiuo, class I molecules can also be induced on neurons by direct intracerebral inoculation of interferon y (Wong et al., 1984) . In oligodendrocytes, interferon-inducible expression of MHC class I1 is lost on differentiation from the oligodendrocyte-type I1 astrocyte (02A) common precursor (Calder et al., 1988 ).

In addition to infection, demyelination may also result from immunization with various combinations of CNS antigens or from exposure to chemicals. These models yield additional information that is relevant to a consideration of viral demyelination.

Experimental allergic encephalomyelitis (EAE) was first produced in monkeys in the 1930s, and has since been demonstrated in many animal species. Experimental allergic encephalomyelitis is characterized by intense focal perivascular inflammation and demyelination in the brain and spinal cord, in response to peripheral inoculation of CNS antigens. Severity of disease corresponds to the degree of delayed-type hypersensitivity to CNS antigens, but not with the levels of circulating anti-brain antibodies. Because disease could be transferred with suspensions of lymph node cells, or purified T cells, it was concluded that this inflammatory condition and associated demyelination were dependent on the presence of CNS antigen-specific T cells (Thomas et al., 1950; Paterson, 1960; Ortiz-Ortiz et al., 1976) . Indeed, it is now well established that extraneural immunization with purified MBP or specific (encephalitogenic) peptides of MBP can induce MBPspecific, class II-restricted T cells that cross into the CNS to produce the characteristic perivascular infiltrates observed in this disease. Furthermore, this inflammatory disease can be initiated by the adoptive transfer of MBP-specific T cell lines and clones (Ben-Nun et al., 1981; Sakai et al., 1986) .

Experimental allergic encephalomyelitis produced by inoculation of purified brain components such as MBP, peptides of MBP, or transfer of MBP-specific T cell clones must be separated from that produced by inoculation of whole white matter. The disease resulting from inoculation of purified MBP or peptides derived from it is not as severe as that produced by inoculation of whole white matter. Sera from animals immunized with whole white matter contain demyelinating activity, but sera from animals inoculated with MBP alone do not (Bornstein and Appel, 1961; . Inoculation of purified oligodendrocytes can also produce EAE, with production of serum antibodies that demyelinate cerebellar tissue cultures and lymphocyte proliferation responses to oligodendrocytes, but not to MBP (Podusolo et al., 1976; McDermott et al., 1977; Raine et al., 1977; Abramsky et al., 1977) .

The demyelinating activity in the sera of animals inoculated with whole white matter or oligodendrocytes correlates with the titer of antibody to the glycolipid galactocerebroside (T. Saida et al., 1977a Saida et al., , 1979  K. , and sera from rabbits inoculated with purified galactocerebroside demyelinates CNS tissue cultures (Dubois-Dalcq et al., 1970; Fry et al., 1974; Saida et al., 197713) . Further, direct inoculation of anti-galactocerebroside antibody into the optic nerve of cats resulted in destruction of oligodendrocytes and demyelination (Carroll et al., 1985) and inoculation of rabbits with bovine brain gangliosides initiated demyelinating encephalitis (Konat et al., 1982) .

Demyelination can be separated from inflammation on the basis of studies of T cell clones. Transfer of syngeneic, MBP-reactive T cell clones to naive rats results in a CNS inflammatory disease with minimal demyelination, whereas transfer of both MBP-reactive clones and antibody to the oligodendrocyte surface antigen myelinloligodendrocyte glycoprotein (MOG) results in a more intense inflammatory response with extensive demyelination Fierz et al., 1988) . It seems likely that although MBP-specific T cells initiate the CNS inflammatory response, the extent of demyelination is related to the production of antibodies to components of oligodendrocytes such as MBP or MOG.

Damage to myelin, including demyelination, can be induced by a variety of chemicals (reviewed by Blakemore et al., 1983) . Chemicals inducing demyelination by destruction of oligodendrocytes include ethidium bromide, lysolecithin, and cuprizone (Spencer and Schaum-burg, 1980; Hall, 1972) . Mice fed on a diet containing cuprizone show pyknotic oligodendrocytes and subsequent demyelination in specific white matter tracts (Blakemore, 1973a) . Degenerating myelin is removed by macrophages. Processes from hypertrophic astrocytes then surround the demyelinated axons, new oligodendrocytes appear, and, on withdrawal of cuprizone, mediate remyelination (Blakemore, 1973b; Ludwin, 1978) . Some chemicals will also destroy astrocytes producing CNS lesions of demyelination void of glial cells. Remyelination of these lesions is slower. Oligodendrocytes reappear within or around the lesion but remyelination does not occur in the absence of astrocytes (Blakemore, 1975) .

Mouse hepatitis virus (MHV) is a member of the Coronaviridae.

These viruses contain a single-stranded message sense genome in excess of 32 kb. Transcription from a full-length replicative intermediate produces a set of 3' coterminal messenger RNAs. The unique 5' sequence of each mRNA is translated. Seven genes have been clearly identified and are numbered 1 to 7, 5' to 3'. Additional open reading frames are present in some viruses but not others and have been designated 2A or 2B, and so on. By far the largest gene at 23 kb (Pachuk et al., 1989) is gene A, the putative viral RNA polymerase. The envelope spike glycoprotein, S, is encoded by RNA 3, the matrix protein, M, by RNA 6 and the nucleoprotein, N, by RNA 7. Gene 2 encodes a hemagglutinin protein that is expressed only in selected strains of MHV. The envelope glycoprotein, S (previously E2), encoded by RNA 3, is posttranslationally cleaved into two 90-kDa glycoproteins known as S1 and S2 (previously E2, 90B and 90A). This glycoprotein contains the major viral neutralizing epitopes and mediates viral receptor binding and fusion. For reviews on the molecular virology of coronaviruses see Siddell et al. (19831, Spaan et al. (1988), and Lai (1990) .

Strains of MHV cause a spectrum of diseases from hepatitis and enteritis to encephalomyelitis with demyelination. Demyelinating strains include MHV-4, A59, and JHM. As with all viruses, pathogenesis and severity of disease are dependent on host and viral genetics and the route and dose of inoculation. The influence of viral and host genetics on the outcome of disease is always complex but is particularly so with MHV. This has been dramatically demonstrated by studies of different laboratory strains, their temperature-sensitive mutants, monoclonal antibody neutralization-resistant variants, and in uiuo and in uitro isolates. Several pathogenic, biochemical, and genetic differences have been observed among the different laboratory strains of MHV and as we will discuss although nominal strain designations may be identical, differential viral properties can evolve in the process of both in uiuo and in uitro laboratory passage (Taguchi et al., 1985; Morris et al., 1989; Gallagher et al., 1990) .

Monoclonal antibody-resistant variants of MHV with altered neurovirulence have been generated by several laboratories. One example is variant V5A13.1 (Dalziel et al., 19861 , selected from wild-type (wt) MHV-4 using a neutralizing monoclonal antibody. The parental MHV-4 wt is highly neurovirulent (LD,, < 0.5 pfu) following intracerebral inoculation, whereas the variant is avirulent (LD,, > 1800 pfu). Others have described similar attenuated neutralization-resistant variants, including JHM wt B35 and JHM-DL 2.2-V-1 (Fleming et al., 1987) . In all of these variants, the neurovirulence of the parental wild-type virus is attenuated but the capacity to induce chronic white matter disease remains.

I n situ hybridization studies have demonstrated that both MHV-4 wt and its V5A13.1 variant predominantly infect neurons (Fazakerley et al., 1992) . Following intracerebral inoculation MHV-4 wt was first detected in neurons of the deep cortical layers. The virus spread rapidly and by 3 days was present throughout the deep cortical areas, in occasional foci in the outer cortex, caudate, olfactory lobe, rhinencephalon, hypothalamus, pons, brainstem, and in the midcerebellar nuclei. The outer layers of the cortex, thalamus, and most of the cerebellum remained largely uninvolved. The infection was almost exclusively neuronal. Meninges, choroid plexi, endothelial cells, and glial cells were rarely infected. This widespread infection was associated with death of the animals within 4 days of inoculation and probably resulted from direct viral destruction of infected neurons. The V5A13.1 variant spread at a slower rate to infect the same areas but with involvement of fewer neurons. The slower rate of spread presumably allowed intervention of the immune response before infection of a lethal number of neurons, and the mice survived to develop a chronic demyelinating disease in which virus persisted in glial cells of the white matter (Dalziel et al., 1986; Fazakerley et al., 1992) .

The JHM-DL strain of MHV also predominantly infects neurons while its derivative, monoclonal antibody-resistant variant 2.2-V-1, infects both neurons and glial cells. Another variant, 2.2/7.2-V-2, infects only glial cells. These variants are avirulent and produce a subacute demyelinating disease (Fleming et al., 1987) . A change from acute lethal encephalitis to subacute demyelinating disease has also been observed between JHM wt and its B35 variant (Wege et al., 1988) .

Demyelination is also seen in animals surviving inoculation with parental MHV-4 of JHM, and in MHV-4-infected animals protected by passive administration of neutralizing monoclonal antibodies (Buchmeier et al., 1984; Perlman et al., 1987) . In the latter case one possibility is that neutralization-resistant variants with avirulent, demyelination-inducing phenotypes are generated in uiuo. Selection of demyelinating variants in uzuo may also occur in rats infected with JHM wt. In one study (Taguchi et al., 1985,19861 , intracerebral inoculation of parental JHM wt virus into 4-tod-week-old Lewis rats and analysis of the brain virus after several days of replication demonstrated an increase in the size of mRNAs 2 and 3 and of the nonglycosylated S glycoprotein (product of mRNA 3). In contrast to the previously described MHV-4 V5A13.1 and JHM-DL 2.2-V-1 variants, the large S, brain-derived JHM variant was more virulent than the parental JHM wt virus (Taguchi et al., 1985 (Taguchi et al., , 1986 . In another study (Morris et al., 1989) , a variant isolated from the spinal cord of infected rats synthesized an S glycoprotein smaller than that produced by the inoculum virus.

Interpretation of these data is complex but has been partially clarified by sequencing studies (Schmidt et al., 1987; Luytjes et al., 1987; Parker et al., 1989) . The longest S protein is that of MHV-4 (1376 amino acids). By comparison, the other strains and variants all have deletions in the same region. Differences between the S proteins of MHV-4 and MHV-A59 are seen not only at the level of the sequence but also in the epitopes defined by monoclonal antibodies (Talbot and Buchmeier, 1985; Fleming et al., 1983) . From coronavirus sequence studies it is clear that the genomes of these viruses are highly variable and that a region of hypervariability exists in the S glycoprotein. This hypervariable region undergoes a high frequency of recombination (Banner et al., 1990) . A scheme of polymerase jumping has been proposed to account for these events (M. M. C. Lai et al., 1987) .

The influence of host (rodent) genes on the pathogenesis of MHV infection has also been studied. Intracerebral infection of most mouse strains with MHV-4 or A59 is lethal, but SJL mice survive. Genetic studies indicate that resistance is governed by a single autosomal recessive gene on chromosome 7 that is not linked to the MHC locus (Knobler et al., 1981) . Other studies have suggested that two genes govern susceptibility. A major determinant of susceptibility appears to be a 110-kDa membrane-associated glycoprotein that serves as a cellular receptor for MHV (Boyle et al., 1987) . This molecule, related t o the carcinoembryonic antigen family of proteins, is expressed in hepatocytes and brush-border cells of susceptible mice (R. K. and has been cloned and shown to be a member of the immunoglobulin supergene family (Dveksler et al., 1991) . Human and ham-ster fibroblast cells, normally resistant to MHV infection, are susceptible when transfected with this gene.

Host genes are also important at other stages of the virus infection. The molecular basis of age-related susceptibility to MHV remains, as for other viruses, an incompletely understood phenomenon. An agerelated susceptibility of rats to the JHM strain correlates with the differentiation state of oligodendrocytes. Replication of virus in primary cultures of oligodendrocytes is inversely related to the levels of 2',3'-cyclic-nucleotide 3'-phophodiesterase, a marker of oligodendrocyte differentiation and myelination (Beushausen and Dales, 1985) . In primary rat CNS cultures, virus replication appears to be confined to a discrete intermediate stage in oligodendrocyte differentiation between the 02A precursor cells and fully differentiated oligodendrocytes, which are both resistant to infection (Wilson et al., 1986; Pasick and Dales, 1991) .

Another area of virus-host gene interaction is at the level of the immune response. The role of the immune response in protection and pathogenesis during MHV infection is incompletely understood and controversial. Results vary between laboratories (strains of the virus), rats and mice, and strains of rats and mice. Strain variation is well demonstrated by differences in the pathogenesis of MHV JHM in Lewis and BN rats. Weanling Lewis rats aged 30 to 35 days inoculated intracerebrally with JHM develop either acute encephalitis or subacute demyelinating disease. In contrast, infected weanling BN rats remain clinically healthy . Virus replicates in the brains of both strains but markedly different pathologies result. In the first few weeks of infection, Lewis rats have large inflammatory plaques throughout the white matter, whereas clinically healthy BN rats have small nodular plaques of demyelination that are associated with astrocytic hypertrophy and an influx of plasma cells. Several weeks postinfection Lewis rats show areas of remyelination but no new plaques of demyelination, whereas BN rats show both remyelination and new plaques of inflammatory demyelination. Viral antigens are present in these late demyelinating lesions.

The difference in these pathologies appears to reside in the immune response. Spread of CNS infection in BN rats is controlled by locally produced antibody (Dorries et al., 1987) . A similar accumulation of plasma cells is not observed in Lewis rats. However, infected Lewis rats demonstrate in uitro lymphoproliferative responses to both virus and MBP. In contrast, these are absent in the BN rats (Watanabe et al., 1983, 19871 , which are also refractive to MBP-induced EAE (Wege et al., 1986) . The basis for T cell unresponsiveness to MBP in both MHV infection and EAE in the BN rat appears t o reside at the initiation of the CNS immune response. MHC class 11, Ia molecules can be induced on astrocytes by either JHM virus or interferon y in Lewis but not BN rats (Massa et al., 1987a,b) . In mice, reduction in brain virus titers during acute MHV JHM infection is also associated with the influx of inflammatory cells and correlates with high levels of CD8 + T cells and natural killer (NK) cells (Williamson et al., 1991) . Protection from a lethal intracerebral dose of MHV-4 can be mediated by adoptive transfer of antibodies, virus-specific CD4 + T cells, or virus-specific CD8+ T cells (Buchmeier et al., 1984; Stohlman et al., 1986; Yamaguchi et al., 1991) , indicating that more than one immunological mechanism is protective. In mice, MHC class I but not class I1 could be detected on cultured mouse astrocytes following infection with MHV A59 (Suzumura et al., 1986) . In a further complication of MHV, MHC interactions, MHV-4 infection of cultured cerebral enothelial cells has been observed to down regulate H2K and up regulate H2D (both class I MHC molecules) and to block, at the transcriptional level, interferon y-induced expression of class I1 molecules (Joseph et al., 1989 (Joseph et al., , 1991 .

The relative roles of direct viral destruction and the immune response in generating the lesions of demyelination appear to vary with the system studied. In rats, lesions of demyelination are observed in infected animals and in infected animals that are immunosuppressed or immunodeficient (Sorensen et al., 1982 (Sorensen et al., , 1987 . In contrast, in one study of C57BL/6J mice infected with MHV JHM DL or 2.2-V-1, immunosuppression prevented development of demyelinating lesions. Lesions could be partially restored by adoptive transfer of naive or MHV-sensitized, MHC-matched, nylon wool-nonadherent spleen cells (Wang et al., 1990) . This is in contrast to previous studies on mice with MHV-4, which concluded that demyelination was directly viral mediated (Weiner, 1973; Lampert et al., 1973) . The possibility that MHV infection generates autoimmune T cell reactions that have a role in the production of demyelinating lesions is raised by the finding of MBP-specific T cells in rats infected with MHV JHM . As in EAE (see Section I,E), transfer of these cells to naive animals results in perivenular, CNS inflammatory, but not significantly demyelinating, lesions. In summary, even for this extensively studied virus we still cannot relate with certainty the mechanism of demyelination; indeed it is likely that this varies and is dependent on a combination of virus and host genetics.

Research is now under way to unravel the events that lead to the CNS remyelination that occurs after MHV-induced demyelination. Changes have been observed in the composition of glial cell populations Armstrong et al., 1990) and the transcription of glial cell genes (Jordan et al., 1989) .

Theiler's murine encephalomyelitis virus (TMEV), like MHV, is a natural, enteric infection of mice. The virus was originally described in 1934 by Theiler following its isolation from a mouse with hind limb paralysis. The virus belongs to the cardiovirus genus of the Picornaviridae. The virions are small (28 nm), nonenveloped, and contain a single positive strand of genomic RNA that is translated to give a single polyprotein. The genome and the polyprotein can be divided into three main regions, which are preceded by a leader protein L. P1 contains the four structural capsid proteins designated lA, lB, lC, and 1D (also known as VPs 4, 2, 3, and 1). The P2 region contains three proteins (2A, 2B, and 2C) of unknown function and the P3 region contains proteins 3A, 3B, 3C, and 3D, which function in RNA replication (3B), proteolytic cleavage of the polyprotein (30, and as the RNA polymerase (3D). For reviews on Theiler's virus see Friedmann and Lorch (1985) , Rodriguez et al. (1987b1, and Nash (1991) .

Isolates other than Theiler's original isolate (TO) have been obtained from around the globe and investigated experimentally. These include strains DA, GDVII, BeAn, Yale, and WW. In mice, strains GDVII and FA produce a n acute encephalitis and are virulent when inoculated intracerebrally, intranasally, or orally. These strains have been shown to produce epizootics of encephalitis (Thompson et al., 1951) . The other strains are comparatively avirulent in adult mice, although all kill neonatal mice.

Theiler passed the original isolate (TO) into weanling mice, reproducing the paralysis (Theiler, 1934) . Inflammatory lesions were present in the brain and spinal cord, being most prominent in the latter. The spinal cords also demonstrated neuronal necrosis, particularly of anterior horn cells, and this poliomyelitis was originally studied as a mouse model of polio (Olitsky and Schlesinger, 1941) . Histopathologically it is characterized by areas of neuronal necrosis, neuronophagia, and microglial proliferation, which are seen throughout the CNS, in the absence of white matter disease. Mice that survive this early poliomyelitis develop a persistent CNS infection with lesions of inflammatory demyelination in the spinal cord (Daniels et al., 1952) . This biphasic disease is characteristic of most of the avirulent brain isolates and passages of Theiler's virus. Strains TO, DA, BeAn, and WW are all capable of inducing a chronic demyelinating disease following intracerebral inoculation.

The nominally avirulent (TO) group viruses are in fact more or less virulent depending on the virus strain, passage history, mouse strain, and the route and dose of the inoculum (Lipton, 1975; Lehrich et al., 1976; Lipton and Dal Canto, 1979a; Powell et al., 1977; Dal Canto and Lipton, 1982) . Adaption to growth in cell culture selects attenuated viruses that in some cases no longer induce the acute poliomyelitis seen with the original brain isolates, although the subsequent chronic demyelination may be more intense (Lipton, 1978; Lipton and Dal Canto, 1979b) . Comparison of DA virus passaged and isolated directly from mouse brain with virus passaged and isolated in vitro demonstrated greater heterogeneity in the in viuo genotype, indicating that specific variants are selected by in vitro passage (Roos and Whitelaw, 1984) . The presence within the CNS of a population of viruses with related but variant genomes is a complicating factor in studying the pathogenesis of all the demyelinating RNA viruses and has been discussed for MHV in Section I1,A.

Despite the genetic variability that probably exists in vivo during infection, genetic studies on representative, cloned genomes and genetically engineered recombinants have begun to elucidate the viral genetic loci responsible for virulence, persistence, and demyelination (reviewed by Brahic et al., 1991) . Complete nucleotide sequences of several different clones of GDVII, DA, and BeAn have now been determined (Ozden et al., 1986; Ohara et al., 1988; Pevear et al., 1987 Pevear et al., , 1988 McAllister et al., 1989; Roos et al., 1989; Fu et al., 1990) . GDVII, DA, and BeAn are 90% identical in their nucleotide sequences and 95% identical in their amino acid sequences. In the GDVII virus, neurovirulence is controlled by at least two loci, one variously mapped to the VP1, L/VP1, or 1B(VP2)/2C region Calenoff et al., 1990; Fu et al., 1990) and one 5' of this region Fu et al., 1990 ) that may be the 5' noncoding region alone . The 5' noncoding region has been found to be a major determinant of neurovirulence in two other picornaviruses, polio virus and mengo virus (La Monica et al., 1987; Duke et al., 1990) . In the studies of Lipton and colleagues (1991) , attenuated recombinants of GDVII that contained only the BeAn 5' noncoding sequences did not persist and could produce only small, early, localized lesions of demyelination, suggesting that chronic, persistent, demyelinating disease is not the inevitable consequence of avirulence. This view is shared by Brahic and colleagues, who have mapped persistence and demyelination to the VP1 region of DA (McAllister et al., 1990; Tangy et al., 1991; Brahic et aZ., 1991) . In contrast, Roos and colleagues suggest that all strains of the virus are capable of persisting and initiating a demyelinating disease if the infection is nonlethal and that there are multiple determinants of persistence and demyelination (Fu et al., 1990; Rodriguez and ROOS, 1992) . The importance of VP1 in demyelination is further illustrated by the reduced replication rate and fewer lesions observed following infection with a DA virus with a single amino acid change at residue 101 of VP1 Zurbriggen et al., 1991) .

As with many viral systems, the extent of the pathology depends not only on the virus, but also on the mouse strain. The most severe demyelinating disease is observed in SJL/J mice, CBA and Swiss mice show an intermediate susceptibility, and AKR, DBA, and BALBic mice show minimal lesions (Lehrich et al., 1976; Lipton and Dal Canto, 1979a) . Genetic studies have indicated that susceptibility to demyelination is linked to the MHC class I gene, H2D ) and two non-MHC genes, one on chromosome 6, close to the T cell receptor p chain locus and one on chromosome 3, near the carbonate dehydratase-2 locus (Melvold et al., 1987 (Melvold et al., , 1990 . The MHC-linked susceptibility does not result from a failure to generate virus-specific, CD8 + , cytotoxic T lymphocytes because these can be isolated from the CNS in both resistant and susceptible mice . The non-MHC-linked susceptibility loci could represent, for example, the virus receptor. Both GDVII and BeAn virus have been shown to bind to a 34-kDa membrane-associated protein on susceptible cells (Kilpatrick and Lipton, 1991) . The pathology of the demyelinating disease is well documented. Inflammatory cell infiltrates, predominantly monocytes, lymphocytes, and plasma cells, are first seen in the leptomeninges and as perivascular cuffs in the spinal cord. In the chronic phase of the disease these are associated with lesions of demyelination that expand throughout the white matter. In the lesions of demyelination axons appear to be preserved, there is marked astrocytic hypertrophy and gliosis, and normal oligodendrocytes can be found. Electron microscopic studies have demonstrated stripping of myelin lamellae by mononuclear cells (Dal Canto and Lipton, 1975) , and macrophages containing myelin debris are present within and around the lesions. With time, the inflammatory response subsides and astrocytic gliosis is the most prominent feature. Remyelination is first apparent shortly after demyelination, increases with time, and is mediated by Schwann cells (Dal Canto and Lipton, 1980) . In one series of ultrastructural studies of chronic demyelination associated with DA and WW virus infections, macrophages were the cells most heavily infected; infection of astrocytes and other inflammatory cells was also seen, but no infection of (or pathological changes in) oligodendrocytes or remyelination by Schwann cells was observed (Dal Canto and Lipton, 1979, 1982; Dal Canto, 1982) . In contrast, WW virus was observed to replicate in oligodendrocytes in mouse CNS organ cultures (Wroblewska et al., 1979) and has been demonstrated to persist in glial cells by in situ hybridization studies (Brahic et al., 1981b; Stroop et al., 1981 Stroop et al., ,1982 . By electron microscopy, DA and BeAn viruses have also been observed to infect oligodendrocytes during the chronic phase of disease (Rodriguez et al., 1983; Blakemore et al., 1988) . In a study of DA virus infection of SJL/J mice, in which virus infection was determined by in situ hybridization and cell types by immunostaining, approximately 25 to 40% of the infected cells were oligodendrocytes, 5 to 10% were astrocytes, and 10% were microglia or macrophages (Aubert et al., 1987) .

Neutralizing antibodies are detectable in the serum within a week of infection and rise slowly (Lipton, 1975) . Intrathecal antibody production occurs (Lipton and Gonzalez-Scarano, 1978) . T cells specific to the virus are detectable early in infection and remain throughout the persistent infection (Rabinowitz and Lipton, 1976) . Both viral antibody titers, viral-specific T cell proliferative responses, and delayedtype hypersensitivity responses are maximal at times of maximum demyelination (Clatch et al., 1985) . Virus-specific, CD8 + cytotoxic T lymphocytes are generated (Pena Rossi et al., 1991; Lindsley et al., 1991) . Despite the presence of high titers of neutralizing antibody and antiviral T cell activity, virus can persist in the CNS for at least a year (Lipton et al., 1984) . Virus can be isolated from the spinal cords of mice with paralysis and demyelination but not from clinically healthy infected mice (Welsh et al., 1990) .

To determine the role of the immune response in viral clearance and protection, various manipulations of the immune system of infected mice have been undertaken. In DA-infected SJL mice, cyclophosphamide or anti-thymocyte serum potentiated the acute grey matter disease, leading to higher brain virus titers, greater dissemination of virus, increased neuronal necrosis, rapid onset of clinical symptoms and increased mortality (Lipton and Dal Canto, 1977) . BeAn infection of thymectomized, CD4 + -depleted, CBA mice increased the mortality to 100% by 4 weeks postinfection (Welsh et al., 1987) . Depletion of CD8+ cells made little difference to survival but did decrease virus clearance from the CNS. Depletion of CD4+ T cells was associated with an inability to produce anti-viral antibody, suggesting that the protective effect of the immune response in the early polio phase of this disease is mediated by anti-viral antibodies. In support of this, both CD4-depleted and athymic nulnu mice can be protected from infection by transfer of anti-viral antibody (Welsh et al., 1990; Fujinami et al., 1989) . However, in another study, both CD4 + and CD8 + T cells were suggested to be important in protecting mice from the acute infection. Increased mortality was observed in DA-infected C57BLIlOSNJ mice depleted of CD3 + , CD4 + , or CD8 + T cells .

The immune response appears to play a n important role in development of the demyelinating lesions, although its role is still contentious. In support of a n immune component, demyelinating lesions are absent, or at least reduced, in mice surviving immunosuppression with cyclophosphamide, anti-lymphocyte serum, or cyclosporin A (Lipton and Dal Canto, 1977; Roos et al., 1982; Rodriguez and Quddus, 1986) . Furthermore, demyelination has been reduced by treatment with anti-Ia antibodies (Friedmann et al., 19871 , depletion of CD4+ T cells in thymectomized mice (Welsh et al., 1987) , and treatment with anti-CD3, -CD4, or -CD8 monoclonal antibodies (Rodriguez and Sriram, 1988; Rodriguez et al., 1991) . In contrast, infected, athymic, nulnu mice have been reported to develop demyelinating lesions (Rosenthal et al., 1986; Love, 1987) . In support of an immunological basis to the demyelination, an investigation of spatial and temporal relationships between viral RNA and changes in CNS-specific transcripts such as MBP and PLP did not indicate any direct correlation (Yamada et al., 1990) .

The possible role of autoimmune responses in the demyelinating lesions is, as with other aspects of Theiler's virus immunology, inconclusive. In one study, neither serum nor splenocytes from infected SJL mice with demyelinating lesions had any effect on myelinated CNS cultures, nor did these cells demonstrate proliferation responses to MBP or spinal cord, nor could they transfer disease to naive recipients (Barbano and Dal Canto, 1984) . In contrast, antibodies and delayed-type hypersensitivity (DTH) responses to myelin and antibodies to MBP have been observed in CBA mice infected with BeAn virus (Welsh et al., 1987; Rauch et al., 1987) . The levels of antibodies to MBP correlated with clinical signs. Antibody cross-reactivity between virus and another myelin/oligodendrocyte component, the glycolipid galactocerebroside, has also been reported (Fujinami et al., 19881, although it is not immediately apparent why these nonenveloped virions should cross-react with a n antibody to a glycolipid; one possibility is a conformational mimicry (Oldstone, 1987) .

Semliki Forest virus (SFV) is a n alphavirus found in Africa (Bradish et al., 1971) . The virology and molecular biology of the virus have been reviewed by Atkins et al. (1985) . The virion is small (50 nm) and the genome consists of a single 11-kb molecule of positive-sense RNA (42s) that acts directly as a message. A smaller subgenomic (26s) message coding for the structural proteins is transcribed from a negative-sense replicative intermediate. The prototype strain has been cloned and sequenced (Garoff et al., 1980) . The structural proteins consist of the capsid protein (C) and three surface glycoproteins (El, 2, and 3). The glycoprotein spikes of the virus are composed of three copies each of E l and E2. The envelope structure of the virus has been visualized at 3.5-nm resolution by reconstruction cryoelectron microscopy (Vogel et al., 1986) . The virus enters cells by receptor-mediated endocytosis. Fusion occurs in the endosome. The virus has been reported to bind to the class I MHC molecule (Helenius et al., 19781, although this finding has not been repeated. The closely related virus, Sindbis, has been demonstrated to bind to a developmentally regulated neuronal protein (Ubol and Griffin, 1991) , which appears to be a laminin receptor.

Several isolations of SFV from mosquitoes are documented and from these, strains of different passage histories have been derived. Experimental infections of mice, rats, guinea pigs, and rabbits have been reported (Bradish et al., 1971) . The natural host for the infection is unknown. Following much use in many laboratories, SFV was thought to be unable to infect humans. However, this appears to be strain dependent, as a case of fatal human encephalitis has been reported in a scientist working with the Osterrieth strain of the virus (Willems et al., 1979) . Presently the virus appears to be responsible for an outbreak of febrile illness in central Africa. Symptoms include severe, persistent headaches and myalgia (Mathiot et al., 1990) . Infection of the mouse has been the most studied and here the virus strains can be designated as virulent (L10, V13) or avirulent [A7, A7(74), A81 in the adult animal (Bradish et al., 1971) . Other strains include the strain sequenced by Garoff and colleagues and designated by them the prototype strain (Garoff et al., 1980) , the avirulent, MRS MP 192/7 strain (Henderson et al., 19701 , and a series of nitrosoguanidine-induced mutants of the L10 strain (Barrett et al., 1980) .

The outcome of infection in mice depends on the strain of the virus and the age and strain of the mice. All strains of virus that have been tested are virulent in neonatal and suckling mice by all routes of inoculation (Bradish et al., 1971) . Replication, predominantly in neurons, results in destruction of these cells (Woodward et al., 1978; Pathak and Webb, 1978) . Central nervous system infection of adult mice with L10 virus results, as in the neonatal and suckling mice, in neuronal destruction and death. In contrast, infection of adult mice with A7(74) virus results in a subacute, demyelinating meningoencephalomyelitis with minimal neuronal destruction, followed by remyelination and complete recovery. Defective interfering viruses have been observed in culture and when inoculated into mice can protect against infection with a lethal dose of virus (Bruton and Kennedy, 1976; Crouch et al., 1982; Barrett and Dimmock, 1984) .

Despite high virus titers in the brains of SFV A7(74)-infected adult mice, electron microscopic studies reveal no maturation of virus and no advanced stages of virus replication, only accumulation of viral nucleocapsid material, predominantly in neurons Webb, 1978, 1988) . This apparent contradiction remains unresolved. Treatment of adult mice with the drug sodium aurothiomalate induces physiological changes in neurons. Infection of such mice with SFV A7(74) results in complete replication of virus within neurons, neuronal destruction, and death ). It appears that replication of the A7(74) strain is blocked within differentiated adult mouse neurons but not in the differentiating neurons of neonatal or suckling mouse brains. Neuronal maturity has also been demonstrated to be an important determinant of susceptibility in rats infected with another alphavirus, Japanese encephalitis virus (Ogata et al., 1991) .

Following intraperitoneal infection of adult mice with the A7(74) strain, virus replicates in smooth and skeletal muscle, resulting in a plasma viremia that is present from the first to the third day of infection (Pusztai et al., 1971) . Virus enters the brain by passage across the cerebral endothelial cells (Pathak and Webb, 1974, 19801 , and is detectable in the CNS by infectivity assay from day 1 to ll Fazakerley and Webb, 1987a) , and by immunocytochemistry for up to 6 months (Khalili-Shirazi et al., 1988) . Virus also persists for many months in the CNS of athymic nulnu mice unable to produce anti-viral IgG or T cell responses (Fazakerley and Webb, 1987b) .

Following intraperitoneal infection, disturbance of the blood-brain barrier, as measured by the IgG index of the CSF, occurs until 7 or 8 days postinfection (Parsons and Webb, 1982a) . This is associated, between days 4 and 10, with a transient pleocytosis (Parsons and Webb, 1982b) . On restoration of the blood-brain barrier, anti-viral antibody synthesis continues locally within the CNS (Parsons and Webb, 1982a) . Demyelination, observed in the brain (Kelly et al., 19821, spinal cord (Pathak et al., 19831 , and optic nerves (Illavia et al., 1982) , is first apparent 9 days postinfection and is maximal at day 14. Remyelination occurs and is apparent by 21 days. Demyelination has been observed in several strains of mice (Suckling et al., 1980) . Electrophysiological studies indicate abnormal visual evoked responses (Tremain and Ikeda, 19831 , changes in axonal transport in demyelinated optic nerve fibers (Pessoa and Ikeda, 1984; Jenkins and Ikeda, 1991) , and abnormalities in retinal neurons (Tansey and Ikeda, 1986 ). There are changes in the levels of neurotransmitter precursors (Bar-rett et al., 1986) and behavioral changes in infected mice (Webb et al., 1979) . Virus infection stimulates both humoral and cellular immunity. Mice immunized with inactivated SFV demonstrate protective, delayed-type hypersensitivity responses that can be transferred to naive animals by lymph node but not spleen cells (Kraaijeveld et al., 1979a,b) . Virus can replicate in macrophages ( Van der Groen et al., 1976) and macrophages produce interferons a and p in response to infection (Blackman and Morris, 1984) . Late in the infection, spleen cells produce interferon y. Anti-viral, cytotoxic T lymphocytes are present in infected mice from day 3 to 10 postinfection (Blackman and Morris, 1984) and can destroy SFV-infected, MHC-positive, primary, murine brain cell cultures (Morris et al., 1987) . Both neutralizing and nonneutralizing monoclonal antibodies directed against the E l or E2 envelope glycoproteins can protect mice against a lethal dose of infection (Boere et al., 1983 (Boere et al., , 1985 .

Neuropathological studies of adult mice infected intraperitoneally with the avirulent A7174) strain demonstrate a predominantly mononuclear cell inflammatory response in the meninges and around vessels. Foci of inflammation and associated demyelination are apparent throughout the brain, but predominate in the cerebellum . There is little or no destruction of neurons, but astrocytic hypertrophy and gliosis are apparent (Chew-Lim et al., 1977; Mac-Kenzie et al., 1978; Kelly et al., 1982) . A detailed electron microscopic study of the development of demyelinating lesions demonstrates early infiltration of lymphocytes, which associate closely with astrocytes, oligodendrocytes, and myelinated axons. In older lesions macrophages can be observed removing the damaged myelin. The axons remain intact. Accumulation of viral nucleocapsids is apparent in neurons (Pathak and Webb, 19881 , and viral antigens are detectable on neurons, particularly in the hippocampus, and on glial cells in the cerebellum (Khalili-Shirazi et al., 1988) .

The inflammatory neuropathology is suggestive of an immune-mediated demyelination and this is supported by immunological studies. Athymic nulnu mice have neither changes in axonal transport, lesions of demyelination, nor neuronal pycnosis, despite persistently high brain virus titers Fazakerley and Webb, 198713; Jenkins et al., 1988) . Adoptive transfer of syngeneic spleen cells to infected nulnu mice restores the lesions of demyelination, and these occur earlier following the transfer of SFV-primed lymphocytes. Intraperitoneal transfer of anti-SFV immune serum does not restore the lesions (Fazakerley et al., 1983; Fazakerley and Webb, 1987b) . Immunosuppression by cyclophosphamide , total body irradiation (Fazakerley and Webb, 1987c) , or cycloleucine (Amor and Webb, 1987) delays or prevents demyelination, although demyelination is not prevented by treatment with cyclosporine (Fazakerley and Webb, 1987a) . This drug probably does not cross the blood-brain barrier (Palestine et al., 1985; Fazakerley and Webb, 1987a) .

Possible mechanisms of demyelination include a T cell response either to viral determinants on the cell surface, or to an autoantigen. Virus-specific, cytotoxic T cells are present in the first 2 weeks of infection (Blackman and Morris, 1984) . At 7 days, lymph node cells respond to MBP in a proliferation assay (Mokhtarian and Swoveland, 1987) . Interestingly, C57B116 mice that have recovered from SFV A7(74) infection are susceptible to MBP-induced EAE, whereas previously uninfected mice are not (Mokhtarian and Swoveland, 1987) . Semliki Forest virus is an enveloped virus and, as with any such virus, takes its envelope lipids from the membranes of the host cell. If virus is grown in mouse brain cell cultures, the envelope contains myelin glycolipids, including galactocerebroside Khalili-Shirazi et al., 1986; Evans and Webb, 1986) .

In addition to the well-studied A7(74) and L10 strains of SFV two mutant viruses, M9 and M136, have been described (Sheahan et al., 1981 (Sheahan et al., , 1983 . The mechanism of demyelination here appears to be different: these mutants destroy G26-24 oligodendroglioma cells in culture and produce demyelination in adult mice by direct destruction of oligodendrocytes (Sheahan et al., 1981 (Sheahan et al., , 1983 Atkins and Sheahan, 1982) .

Two related alphaviruses, Ross River virus (RRV) and Venezuelan equine encephalitis viruses (VEEV), also produce experimental demyelination in mice Wolinsky, 1982, 1983; Dal Canto and Rabinowitz, 1981a) . Extraneural inoculation of the T48 strain of RRV produces focal lesions of inflammatory demyelination and necrosis throughout the brainstem, cerebellum, and spinal cord (Seay and Wolinsky, 1982) . Electron microscopy demonstrates that oligodendrocytes are the primary site of viral replication, but virus is also found in subpopulations of neurons and in invading polymorphonuclear leukocytes and macrophages. Demyelination occurs within 3 days of infection, increases with increasing brain virus titer, is not prevented by immunosuppression with cyclophosphamide, and probably results from either a direct effect of the virus on the oligodendrocytes, or the virally induced release of toxic factors. Remyelination occurs and is not mediated by migrating Schwann cells Wolinsky, 1982,1983) . The situation with VEEV is different and more akin to that described for the A7(74) strain of SFV. Venezuelan equine encephalitis virus produces inflammtory lesions of primary de-myelination in the spinal cord of infected mice. Lesions are absent in nulnu mice, suggesting a n immune-mediated demyelination (Dal Canto and Rabinowitz, 1981a) .

Visna virus belongs to the lentivirus group of retroviruses. The name of the virus derives from the Icelandic name given to the wasting, demyelinating neurological disease it causes in sheep. The infectious visna virus is an enveloped RNA virus, but the viral life cycle also involves a DNA proviral stage. The provirus is detectable within an hour of infection (Haase et al., 1982) . Different strains of visna and the closely related caprine arthritis encephalitis virus (CAEV) have been sequenced (Sonigo et al., 1985; Saltarelli et al., 1990; Querat et al., 1990; Sargan et al., 1991; Staskus et al., 1991a) . The viral genome is a positive strand of polyadenylated RNA of approximately 9 kb that contains three structural genes, gag, pol, and enu, 5' to 3'. In addition there is a series of small open reading frames between and overlapping these genes that code for regulatory proteins. The gag gene is translated into a polyprotein that is cleaved to give the three components of the virus core. The enu gene appears to code for a 90 to 100-kDa precursor envelope glycoprotein that is processed and highly glycosylated to produce the major surface glycoprotein gp135. (Vigne et al., 1982; Sonigo et al., 1985) . Visna virus appears to bind to the cell surface sheep MHC class I1 molecule . The pol gene product, as with other lentiviruses, encodes the viral reverse transcriptase (Sonigo et al., 1985) .

The virology of visna virus has been reviewed by Nathanson et al., (19851, Haase (19861, Narayan et al. (19881, Clements et al. (1988) , and Cheevers and McGuire (1989) . Natural infection is by the respiratory route, by which the virus also causes the more common chronic pulmonary disease of sheep, known in Iceland as rnaedi and in North America as progressive pneumonia. Infection of lambs also occurs through colostrum. There is no evidence of germ-line transmission. Visna normally occurs in Icelandic sheep as a neurological complication of maedi. The disease is rarer in sheep of other breeds. Epidemics in Icelandic sheep have been related to the confined, close housing of animals (Gudnadottir, 974) . The closely related CAEV is found world wide in goats, and produces both arthritis and demyelination.

Serological studies indicate that infection may be as high as 80-85%, with estimates for the prevalence of clinical disease varying from low to about 25% of the seropositive population (Adams and Gorham, 1986; East et al., 1987) . Clinical disease is commonly apparent 2 years or more after infection and results in death, usually within a year (Sigurdsson, 1954; Oliver et al., 1981) .

Visna was originally isolated from Icelandic sheep (Sigurdsson et al., 1960) , but subsequent isolations have been made from sheep in several countries. The different isolates differ somewhat in their properties. The prototype virus isolated by Sigurdsson et al. and a North American isolate (Cutlip and Laird, 1976) replicate to high cell-free titers and are cytolytic in a sheep choroid plexus cell line in uitro, whereas most North American field isolates establish persistent, syncytium-forming infections with low or undetectable levels of cell-free virus (Narayan et al., 1982) . Addition of macrophages or monocytes to cultures of persistently infected, sheep choroid plexus cells results in productive, cytolytic infection of the latter (Narayan et al., 1982; Anderson et al., 1983) .

Persistent infection occurs in uiuo and virus can be found in several organs, throughout life, despite the presence of neutralizing antibody.

For example, in situ hybridization has been used to detect polymerase chain reaction (PCRI-amplified viral sequences in fixed tissues, including bronchiolar epithelial cells and alveolar macrophages (Staskus et al., 1991b) . Infection of monocytes and macrophages is particularly important in the pathogenesis of visna as monocytes are the likely mechanism of virus distribution between tissues . The maturation of virally infected monocytes to macrophages is associated with an increase in viral gene expression. Migration of infected monocytes across the blood-brain barrier is a likely mechanism of virus entry into the CNS. Another mechanism of viral entry into the CNS is via the choroid plexi. I n situ hybridization studies of choroid plexus cells infected in uiuo indicate the presence of proviral DNA in up to 3% of cuboidal epithelium cells. Immunofluorescence studies detect only rare positive cells in the choroid plexus, and comparison of the levels of DNA and RNA in these cells indicates that viral expression is blocked in these cells at a transcriptional level (Haase et al., 1977 (Haase et al., , 1982 Brahic et al., 1981a) .

Maedi has been characterized as a lymphoproliferative interstitial pneumonia. The alveolar septae contain numerous inflammatory cells, which in severe cases can form germinal centers. Likewise, neurological disease (visna) involves a predominantly mononuclear cell meningoencephalomyelitis with infiltration of cells around the vessels and formation of germinal centers in the choroid plexus (Sigurdsson et al., 1962; Oliver et al., 1981) . Neurons are rarely destroyed. Astrocytic gliosis and demyelination are apparent.

The course of infection and the neuropathogenesis of visna virus have been studied experimentally in Icelandic sheep (reviewed by Nathanson et al., 1985) . Intracerebral inoculation results in a persistent, cell-associated viremia, first detectable at 2 to 4 weeks postinfection . Virus is present in very few cells. Isolation of virus by cocultivation with sheep choroid plexus cells indicates that as few as 1 in 1 million cells, lymphocytes, and macrophages actively produces infectious virus (Petursson et al., 1978; Narayan et al., 1982) . Cocultivation studies indicate that virus also persists throughout life in the lungs, lymphoid tissues, and CNS . The difficulty of virus isolation suggests that virus persists in the proviral state and that very little infectious virus is produced. Neutralizing serum antibodies first appear 2 to 3 months postinfection and persist for life . Oligoclonal, neutralizing antibody, predominantly IgM, is produced by plasma cells in the CSF (Georgsson et al., 1977; Nathanson et al., 1979; Martin et al., 1982) .

Within a few weeks of the experimental, intracerebral infection of Icelandic sheep, a subclinical meningoencephalomyelitis is apparent. This correlates in severity with that of a mononuclear cell pleocytosis, first detectable within months of infection (Nathanson et al., 1979) . The early lesion consists of infiltrating lymphocytes, monocytes, macrophages, and plasma cells, in which neuronal destruction, necrosis, and demyelination are rare (Georgsson et al., ,1977 . There is a correlation between the infecting dose of virus, the CNS titer at times postinfection, and the severity of the early inflammatory response . Clinical signs, usually progressive paresis, first appear from 3 months to 8 years and may depend on the strain of the virus (Petursson et al., 1978; Lutley et al., 1983) . Clinically affected animals have focal lesions of primary demyelination in the brain and spinal cord . These vary in their degree of inflammation and gliosis and probably represent the difference between young and old lesions.

Unlike demyelinating virus infections of the rat and the mouse, it has not been possible in the sheep to separate the role of the virus and that of the immune response in the pathogenesis of the disease. However, Nathanson and co-workers (1976) were able to suppress the early, nondemyelinating inflammatory lesions using anti-thymocyte serum. This did not change the frequency of virus isolation, nor in the absence of T cell immunity was there any evidence of direct virus-induced destruction of CNS cells, indicating that the early inflammatory response probably confers no benefit, only damage. This finding suggests that demyelination does not result from direct destruction of oligodendrocytes; however, the immunosuppression experiments address only the early lesions, and the situation may change as the pathology progresses to include demyelination. Infection of oligodendrocytes has been shown by in situ hybridization of a visna virus-specific probe to cells stained with anti-oligodendrocyte antibodies (Stowring et al., 1985) . The number of infected cells does not correlate with the extent of the demyelinated lesions, leading to speculation that infection of oligodendrocytes may induce and maintain an immune response to these cells (Nathanson et aZ., 1985) . Lymphocytes taken from sheep up to 2 years postinfection demonstrate normal responses t o mitogens, but no response to myelin basic protein by proliferation assay . Neither do these sheep have antibodies to galactocerebroside. The composition of the inflammatory lesions in whole brain-induced EAE in the sheep is similar to that seen in visna, but the distribution of the lesions is different, and lymphocyte proliferation to MBP and antibodies to galactocerebroside are present . The mechanism of demyelination in visna remains to be determined but results to date are more suggestive of an immune-mediated mechanism than of direct virus destruction.

Canine distemper and old dog encephalitis are natural, demyelinating diseases of dogs produced by the same virus (Imagawa et al., 1980) . Canine distemper virus is a member of the morbillivirus group of the Paramyxoviridae and as such is related to measles. Like visna virus in sheep, canine distemper has been studied experimentally. Animals can be infected intraperitoneally or intranasally . The course and outcome of infection are variable. Neurological signs may present within days to months, the time of onset appearing to correlate with age. Inflammatory and noninflammatory lesions of demyelination are observed and the type of lesion is probably related to the degree of virus-induced immunosuppression. Immunosuppression has been observed in some animals as a decrease in lymphocyte responses to mitogens (Krakowka et al., 1980; Vandevelde et al., 1982a; Cerruti-Sola et al., 1983 ) and a severe lymphocytopenia is sometimes observed (McCullough et at., 1974; Krakowka et al., 1975 Krakowka et al., , 1980 . Nevertheless, some dogs are able to mount a rapid immune response, preventing widespread viral dissemination in the CNS. This results in no or small focal lesions of demyelination that may or may not be inflammatory; such animals quickly recover (Appel et al., 1982; Cerruti-Sola et al., 1983) . Animals with persisting immunosuppression and chronic noninflammatory demyelination have also been observed . Between these two extremes are animals with varying degrees of immu-nosuppression; they may or may not develop early noninflammatory lesions of demyelination, but progress to lesions of inflammatory demyelination of varying severity (Krakowka et al., 1980; Appel et al., 1982; Cerruti-Sola et al., 1983; Summers et al., 1987) . An important question has been the role of the immune response in these late inflammatory lesions. The outcome in such dogs ranges from viral clearance, recovery, and remyelination (McCullough et a1 ., 1974; Vandevelde et al., 1985) to severe demyelination and white matter necrosis.

The early plaques of demyelination are focal, periventricular, often noninflammatory, and are suggestive of a direct effect on glial cells (Raine, 1976; Summers et al., 1979; Vandevelde et al., 1982b Vandevelde et al., , 1983 Vandevelde et al., , 1985 . Viral infection, viral inclusions, probably nucleocapsids, and the expression of all four four viral structural proteins (N, P, F, and H) have been observed in astrocytes, neurons, macrophages, meningeal, ependymal, and choroid plexus cells, a s well as in invading lymphocytes (Wisniewski et al., 1972; Mitchell et al., 1991) , but not, or rarely (Raine, 1976) , in oligodendrocytes. Consistent with this finding is the infection of astrocytes but not oligodendrocytes in primary brain cell cultures . However, destruction of both cell types occurred in these cultured explants, leading to the suggestion that destruction of oligodendrocytes in this disease is mediated by the release of toxic factors from other CNS cells . Demyelination has been suggested to result from infection and perturbation of astrocyte functions, leading to edema and ballooning of myelin sheaths (Summers and Appel, 1987) , and astrocyte hypertrophy early in disease has been described (Summers et al., 1979; Summers and Appel, 1987) .

In most animals progressing to chronic disease, and in some animals with subacute disease, the demyelinating lesions are inflammatory and invading mononuclear cells strip myelin lamellae from axons and phagocytose myelin debris (Wisniewski et al., 1972) . Disturbance of the blood-brain barrier and intrathecal antibody synthesis occur in dogs with inflammatory demyelinating lesions . Antibodies to virus and myelin are present in both serum and CSF (Krakowka et al., 1973 (Krakowka et al., , 1975 Vandevelde et al., 1982a Vandevelde et al., , 1986 . Bound antibody has been demonstrated in lesions of demyelination. Levels of MBP in the CSF correlate with the clinical and pathological course of the inflammatory disease (Summers et al., 1987) .

In addition to the humoral response, a cellular immune response to the virus occurs (Appel et al., 1982) and in some experimentally infected dogs a cellular response to myelin antigens is also present . Both the cellular and the humoral immune responses to myelin occur in dogs with and without visible lesions of demyelination, leading to the suggestion that immune responses to myelin in this disease are epiphenomena (Cerruti-Sola et al., 1983) . A comparison of the neuropathology of canine distemper and canine EAE also led to the suggestion that autoimmunity to myelin is not an important component of this disease, because the distribution and composition of the lesions differ in these two conditions (Summers et al., 1984) .

A paramyxovirus also causes demyelinating disease in cats. A natural, subclinical, inflammatory, demyelinating disease has been observed in 7% of stray domestic cats examined in Perth, Australia (Cook, 1979; Cook and Wilcox, 1985) . Focal lesions of demyelination of various size are present throughout the brain and optic nerves. Oligodendrocytes on the edge of lesions have vesiculation of the rough endoplasmic reticulum, and paramyxovirus-like nucleocapsids have been described within glial cells (Cook, 1979; Cook and Wilcox, 1985) . The same inclusions were seen in indicator cells cocultivated with CNS tissue from cats with lesions of demyelination (Wilcox et al., 1984) . Such cultures became persistently infected with little cytopathic effect. Antibodies raised to the purified cytoplasmic inclusions stained similar inclusions in MS plaques (Cook et al., 1986) .

Herpes viruses are ubiquitous DNA viruses found in association with neural tissues throughout the vertebrate animals. The viruses are large and complex and have in excess of 70 genes, with a genome in excess of 150 kb (McGeoch et al., 1988) . Several of these viruses have been associated with demyelinating disease. Demyelination associated with herpes simplex virus type I (HSV-I) has been studied in both mice and rabbits Kristensson and Wisniewski, 1978) . Herpes simplex virus type I1 also produces demyelination in mice following direct intracerebral or genital infection, with lesions in the brain, spinal cord, and optic nerves (Martin, 1982; Martin and Stoner, 1984) . Mareks disease of fowl is characterized by peripheral nerve demyelination following infection with a herpes virus (reviewed by Payne, 1982) .

In mice, footpad, corneal, facial, or pinna infection with HSV-I results in focal demyelination of axons in the corresponding root entry zone in the CNS (Baringer and Swoveland, 1973; Baringer, 1976, 1978; Kristensson et al., 1978 Kristensson et al., , 1979 Hill, 1983) . The virus spreads intraaxonally without producing demyelination or any other damage in the transporting peripheral nerves (Cook and Stevens, 1973; Kristensson et al., 1979) . Schwann cells in the region of the ganglia, but not those within the nerve itself, can become infected but do not release mature virus (Rabin et aZ., 1968; Cook and Stevens, 1973) . However, in one report, replication and release of mature virions from Schwann cells and lesions of inflammatory demyelination were observed after direct microinjection of virus into the sciatic nerve (Townsend and Collins, 1986) .

On reaching the CNS, HSV-I replicates in and destroys astrocytes in the root entry zone (Townsend, 1981; Itoyama et al., 1991) and necrotic, hemorrhagic, inflammatory, demyelinating lesions are produced . Viral destruction of oligodendrocytes may occur (Kristensson et al., 1979) and virus has been shown to replicate in these cells in vitro (Kastrukoff et al., 1987) . Schwann cell remyelination occurs in the demyelinated lesions on the CNS side of the root entry zone (Townsend, 1983) . Virus can become latent within the trigeminal or dorsal root ganglion (Kristensson et al., 1979; Stroop et al., 1984) .

Experimental infection of mice with temperature sensitive (ts) mutants of two rhabdoviruses, Chandipura virus and vesicular stomatitis virus (VSV), has been shown to produce CNS demyelination. The ts472 strain of Chandipura virus and the tsF41 and G32 strains of VSV produce extensive inflammatory demyelination in the spinal cords of infected mice . In both cases, no demyelinating lesions are present in nulnu mice, although high brain virus titers, foci of necrosis, and extensive gray matter degeneration occur Dal Canto and Rabinowitz, 1981b) .

The use of live attenuated measles virus vaccines has resulted in virtual elimination of this virus in the United States (reviewed by Hinman, 1982) . However, measles remains a major health problem in many other countries. Encephalomyelitis is an important complication of measles, occurring in about 1 in 1000 cases (Johnson et al., 1978) . Neurological signs follow acute infection within days to weeks. This postinfectious encephalomyelitis is characterized by a perivenular mononuclear cell inflammation and demyelination. The neuropathology resembles that seen in EAE. Myelin basic protein levels in the CSF correlate with disease progression, and lymphocyte proliferation responses to MBP are present in some patients (Lisak et al., 1974; Johnson, 1982) . The likely autoimmune nature of this disease is reinforced by the failure to detect measles virus, measles antigens, or measles antibody in the CNS Gendelman et al., 1984) .

Postinfectious encephalitis with perivenular demyelination also occurs as a rare complication of vaccinia, varicella, and rubella infections (Spillane and Wells, 1964; Griffith et al., 1970) and probably also occurred in smallpox (Marsden and Hurst, 1932) . In contrast to the situation with measles virus, vaccinia and varicella have been recovered from brains and CSF (Angulo et al., 1964; Brooks et al., 1979; Peters et al., 1978) . Central nervous system demyelination has also been documented following mumps, influenza, and Epstein-Barr virus infections (Schwarz et al., 1964; Hoult and Flewett, 1960) .

Subacute sclerosing panencephalitis (SSPE) is found worldwide and predominates in young males. It is a rare disease affecting perhaps 1 in 1 million children per year. There is no association with HLA type (Aysun et al., 1983) . The disease occurs years, sometimes many years, after acute measles encephalitis. The average age of onset is between 7 and 8 years, and the disease is fatal within months to years (Detels et al., 1973) . Pathologically the disease is characterized by a mild meningitis, perivascular cuffing, gliosis, and varying degrees of demyelination. Eosinophilic inclusion bodies are seen in several cell types but particularly oligodendrocytes, which contain measles nucleocapsids (Greenfield, 1950; Bouteille et al., 1965) . Measles virus antigens are detectable in both neurons and glia (Connolly et al., 19671 , and measles virus has been isolated from some biopsies by cocultivation with nonneural cells (Horta-Barbosa et al., 1969; Payne et al., 1969; Katz and Koprowski, 1973) . Measles inclusion body encephalitis (MIBE), a clinically similar disease with a shorter incubation time, is associated with immunosuppression (Roos et al., 1981) . In SSPE but not MIBE there are high serum antibody titers to all the measles virus proteins except the matrix (MI protein and the CSF contains oligoclonal IgG and elevated titers to measles virus (Wechsler and Fields, 1978; Hall et al., 1979; Dorries et al., 1988) . Measles virus antibody complexes have been detected on CNS cells, myelin, and in cerebral blood vessels, CSF, sera, renal glomeruli, and skeletal muscles (Dayan and Stokes, 1972; Jenis et al., 1973; Perrin and Oldstone, 1977; O'Regan et al., 1979; Sotrel et al., 1983) . Anti-viral antibody may modulate the immune response by removing viral antigens from the surface of infected CNS cells (Fujinami and Oldstone, 1979) .

proteins. The most common finding is absence of M protein expression (Hall and Choppin, 1981; Baczko et al., 1984; Liebert et al., 1986) . Altered protein expression is associated with changes in levels of viralspecific transcripts within infected cells . In one study, sequencing of clones of measles virus genes from SSPE and MIBE brains demonstrated that mutations occurred in most genes with a frequency as high as 2% of all bases although the most dramatic changes were seen in the M gene .

Measles virus infection of the rat CNS has proved to be a good model system for elucidating the molecular changes that give rise to restricted viral gene expression. Restricted expression of viral genes has been demonstrated both in rat brains and in primary rat brain CNS cell cultures and is associated with polarized attenuation of transcription (Schneider-Schaulies et al., 1989 . Interestingly, passive transfer of anti-hemagglutinin antibodies to rats has been shown to modulate viral gene transcription within infected cells and convert the disease from acute to subacute encephalitis (Liebert et al., 1990a) . The mechanism of this action remains unknown but is of interest given the high levels of measles virus antibodies present in SSPE.

The mechanism of demyelination in SSPE remains unknown but given that there is restricted viral replication in oligodendrocytes and that T cell responses to measles are normal in SSPE, viral perturbation of oligodendrocyte cell function, cell destruction as a consequence of occasional productive bursts of complete virus replication, and T cell-mediated destruction of infected oligodendrocytes are all possibilities. In rats, measles virus infection can generate T cell responses to MBP (Liebert et al., 1990b) .

Progressive multifocal leukoencephalopathy (PML), first described in 1958, is a rare opportunistic human demyelinating disease associated with immunosuppression and lymphoproliferative diseases such as Hodgkin's lymphoma and chronic lymphocytic leukemia. The disease is found worldwide. Two related papovaviruses, JC and simian virus 40 (SV40), have been isolated from PML brains (Padgett et al., 1971; Weiner et al., 1972) although JC virus appears to be responsible for the majority of cases (Walker, 1978) . Most populations have a high incidence of JC virus antibodies although this ubiquitous virus has not been associated with any other disease. In PML, high numbers of viral particles are present in the brain (Dorries et al., 1979) . Viral nucleic acid has been detected in oligodendrocytes, astrocytes, and cerebral endothelial cells by in situ hybridization (Dorries et al., 1979) . Focal lesions of demyelination result from destruction of oligodendrocytes (Astrom et al., 1958; Walker, 1978; Johnson, 1983 ). This appears to be a direct consequence of virus infection because abnormal astrocytes and oligodendrocytes around the periphery of lesions contain large inclusion bodies and are positive for viral nucleic acid (Dorries et al., 1979; Shapshak et al., 1986 ). It has not proved possible to study the disease experimentally. J C virus produces no disease in mice (Tooze, 198l> , although the virus produces cerebral tumors in hamsters (Padgett et al., 1977) . However, dysmyelination was observed in mice transgenic for J C virus early region genes under the control of the viral promoter. This was associated with high levels of viral T antigen mRNA in the brain, raising the possibility that early viral gene products impair the function of oligodendrocytes such that they fail to produce myelin (Small et al., 1986) .

Approximately 10% of all AIDS patients present with a neurological disorder. Peripheral neuropathy has been noted in up to 20%, encephalopathy is clinically apparent in over 50%, and at autopsy in 75% of patients (Anders et al., 1986; Parry, 1988; Dalakas et al., 1988) . Clinical symptoms and pathological findings are many and varied but include both peripheral and CNS demyelination (Lipkin et al., 1985; Cornblath et al., 1987; Hollander and Stringari, 1987) . Human immunodeficiency virus has been isolated from peripheral nerves and demonstrated by electron microscopy in peripheral nerve axons .

In the CNS, HIV is found predominantly within macrophages, microglial cells, and multinucleate giant cells, occasionally in endothelial cells and possibly, but rarely, in glial cells. Neuronal infection does not occur (Epstein et al., 1984; Sharer et al., 1985; Koenig et al., 1986; Gray et al., 1987; Kure et al., 1990) . Human immunodeficiency virus can be isolated from the cerebrospinal fluid . Studies on the CSF have also demonstrated intrathecal oligoclonal immunoglobulin synthesis with antibodies to HIV gp41 and p24 Resnick et al., 1985; Goudsmit et al., 1987) . In one study of AIDS patients (Wiley et al., 19881 , HIV was detected by immunocytochemistry with a monoclonal antibody to gp41 in 37 of 93 brains examined. Three brains also showed JC virus in oligodendrocytes by in situ hybridization. These brains had severe lesions of demyelination and other changes characteristic of PML. Of the 93 brains examined, 31 were positive for cytomegalovirus (CMV) by immunocytochemistry; 22 of these were also positive for HIV. Coinfection of individual CNS cells by these two viruses has been demonstrated . Other opportunistic CNS infections seen in AIDS patients include herpes simplex, toxoplasmosis, and cryptococcosis. Onset of neurological symptoms in AIDS can occur at various times from the presenting symptom in otherwise asymptomatic infections to late in the disease (Snider et al., 1983; Nielsen et al., 1984; Navia et al., 1986) . At autopsy brains show a minimal inflammatory response that is predominantly perivascular and composed mostly of macrophages often infected with HIV. Multinucleate giant cells are characteristic and probably result from fusion of infected macrophages and microglia. Microglial nodules, which may be associated with CMV infection, are also present (Wiley and Nelson, 1989 ).

Central nervous system demyelination is not a consistent finding in AIDS patients, although vacuolation of white matter is a more common finding (Shaw et al., 1985; Petito et al., 1985) . The amount of HIV detected in the CNS by nucleic acid probes or antibodies is not proportional to the neuropathology, leading to suggestions that the latter results from factors in addition to the direct effect of HIV. Immunological mechanisms, release of cytokines, and blood-brain barrier changes have been postulated to be involved in the pathogenesis (Wiley and Nelson, 1989; Robbins et al., 1987) . Human immunodeficiency virus infection of mononuclear cells results in their production of various cytokines, including interleukins 1, 6, and 8, TNF-(Y and p, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Merrill et al., 1989; Nakajima et al., 1989; Vyakarnam et al., 1990) . Interleukinl and TNF-a have been demonstrated to damage and destroy oligodendrocytes and myelin in culture (Selmaj and Raine, 1988) . The mechanism of demyelination is not at all clear at this time. J C virus is clearly present in a minority of cases and produces a typical PML disease with demyelination resulting from JC virus destruction of oligodendrocytes. It is possible that J C virus is present in a larger number of patients and is responsible for much of the demyelination seen in AIDS patients. Similarly, the glial nodules could result from CMV infection of the CNS following immunosuppression. Microglial nodules associated with CMV are seen in the CNS following other forms of immunosuppression (Wiley and Nelson, 1989) . One possibility is that HIV-infected macrophages infiltrate the CNS in response to other infections such as JC, CMV, or HSV, and contribute little directly to the neuropathology (Wiley and Nelson, 1989 ).

Another retrovirus that has been associated with human demyelinating disease is HTLV-I. This virus is asymptomatic in most infected individuals but is also the cause of adult T cell leukemia and the demyelinating disease HTLV-I-associated myelopathy (HAM), also known as tropical spastic paraparesis (TSP). These diseases are found in HTLV-I endemic areas, including Japan, the Caribbean, South America, and central Africa. For a review on this virus see Cann and Chen (1990) . Lesions of inflammatory demyelination that include fiber loss have been observed in the spinal cord and optic nerves (Moore et al., 1989) . The close clinical resemblance of HAM and TSP to MS has led to a search for related retroviruses in this disease. In MS, HTLV-I and HIV sequences are absent both by in situ hybridization and PCR. Antibodies to HTLV-I envelope proteins are also absent Hauser et al., 1986; Ehrlich et al., 1991) .

Much research into virus-induced demyelination of the CNS has been aimed at understanding the human demyelinating disease multiple sclerosis (MS), and many of the features observed in the experimental animal systems are seen in this disease. The epidemiology of MS is suggestive of an environmental factor, possibly a virus, and numerous viruses have been associated with this disease by serology, isolation, or pathological study of CNS tissue. Susceptibility is linked to the MHC, specifically the DR2 locus (Dupont et al., 1977; Batchelor et al., 1978) . As with the virus models discussed above, MS is characterized by inflammatory lesions of CNS demyelination with no involvement of the peripheral nervous system. Antibodies and T cell responses to a number of viruses and to CNS antigens have been widely reported. No single virus has been consistently associated with this disease either by isolation or serology.

The above descriptions of experimental animal systems of virusinduced CNS demyelination indicate the important determinants of disease, which include factors controlled by the genetics of the virus, the genetics of the host, and the environment. The strain of the virus, the route and dose of exposure, and interaction with numerous host genes are all important and we will consider each in turn.

The importance of the virus genetics in determining the outcome of CNS disease is well illustrated by attenuated vaccine viruses such as that for polio, which produces a subclinical infection rather than the paralysis associated with natural infection. Sequencing of the entire genome of poliovirus type 3 has demonstrated that change of a single nucleotide from cytosine to uracil in the 5' noncoding region abolishes the ability of this virus to replicate in mouse brain and renders the infection avirulent (La Monica et al., 1987) . Similarly, single nucleotide changes affecting neuropathogenesis have been reported for the CVS strain of rabies virus, reovirus type 3, and the SA AR86 strain of Sindbis virus (Seif et al., 1985; Bassel-Duby et al., 1986; Russell et al., 1989) .

The genetic differences between demyelinating and nondemyelinating, often virulent, strains of the animal model viruses discussed above are not completely clear in any case. The best understood is Theiler's virus, where the availability of infectious clones of the different strains and the ability to engineer recombinants with this small positive-sense genome has allowed mapping of some of the determinants of neurovirulence, although even in this system some debate remains (Calenoff et al., 1990; Fu et al., 1990; Brahic et al., 1991; . Mouse hepatitis virus variants have been mostly selected by their resistance to neutralization with monoclonal antibodies. Given this selection pressure, it is likely that genetic changes between variant and parental virus are to be found within the envelope glycoproteins. The coronaviruses have two glycoprotein spikes, HE and S , encoded by genes 2 and 3, respectively. Direct RNA sequencing of the S gene in MHV-4 and its V5A13.1 variant have determined that the variant has a deletion, relative to the parental virus, of 142 amino acids in the S1 molecule (Parker et al., 1989) . While it is likely that this change in gene 3 influences the outcome of infection from rapidly lethal encephalitis t o subacute demyelination, the effect of other changes in this large (> 32 kb) and highly changeable genome cannot be ruled out. To date infectious clones of this long genome are not available for sophisticated genetic studies. Analysis of the genetic basis of the difference in neurovirulence between strains of SFV is impeded by the lack of sequence data and infectious clones of the most studied virulent (L10) and avirulent, demyelinating [A7(74)] strains. Unfortunately, the pathogenesis of the sequenced prototype strain has been little studied.

Sequencing studies of cloned measles virus transcripts isolated from two patients with SSPE demonstrated change of 2% of the nucleotides in the structural genes (M, F, and HN), relative to the reference Edmonston strain . Variation between clones derived from the same brain was 0.16% of the nucleotides. Changes found during persistent measles virus infections include altered ratios of viral transcripts, changes in the reading frame of the fusion gene, sequence deletions, decreased expression of hemagglutinin, fusion, and matrix proteins, and absence of matrix protein (Lin and Thormar, 1980; Hall and Choppin, 1981; Norrby et al., 1985; Liebert et al., 1986; Cattaneo et al., 1987 Cattaneo et al., , 1988 RNA genomes undergo rapid change (reviewed by Holland et al., 1982; Smith and Inglis, 1987) . The frequency of mutations in RNA genomes is estimated to be on the order of t o lop4 changes per base. Given that the titer of virus in an infected brain can exceed 108 pfu, a single brain could contain on the order of lo4 different genotypes, and for a genome of 11 kb (e.g., alphavirus), genotypes with base changes at every possible site would likely be present. The possibility must be considered that variants with a demyelinating phenotype arise and are selected in uiuo, and in this way many common viruses can occasionally produce neurological, including demyelinating, disease. The isolation from the brains of rats with demyelinating disease of variants of mouse hepatitis virus with changes in gene 3, relative to the inoculum virus, may be an example of in uiuo selection of virus with an altered demyelinating phenotype (Morris et al., 1989) . In uiuo generation of variant viruses has also been observed with LCMV, visna, and HIV (Ahmed and Oldstone, 1988; Clements et al., 1988; Hahn et al., 1986) . Clearly, demyelination, as with any other viral-associated pathology, is determined by the viral genotype and changes as small as one nucleotide could result in a demyelinating disease as opposed to systemic or acute lethal CNS disease. The possibility that occasional viruses with a demyelinating phenotype are selected from a population of in viuo-generated genotypic variants derived from a nondemyelinating phenotype must be considered.

The phenotype of a virus that results in demyelinating disease is complex. Important properties are likely to include an ability to replicate extraneurally, spread t o the CNS, attach to, enter, and replicate in CNS cells, and destroy or perturb the functioning of these cells. Interaction with the immune response will also be of much importance. Change at any stage of any of these processes as a result either of a change in viral genotype (variant selection, as discussed above) or change in the host could result in demyelination by a virus otherwise unassociated with this pathology.

The virus must first gain access to the host and initiate an infection. This stage will depend on the dose of the virus and the mechanism of exposure. Epidemics of demyelinating disease are well known. Visna virus produces epidemics in Icelandic sheep, and these have been related to the confined, close housing of animals and the spread of aerosol virus in respiratory exudates (Gudnadottir, 1974; Narayan and Cork, 1985) . Marek's disease herpes virus, a demyelinating virus of fowl, can decimate poultry farms (Purchase, 1975) . Chickens become persistently infected and release virus from the feather-follicle epithelium, in feces, and in respiratory exudates (reviewed by Payne, 1982) . Epidemics of human demyelinating disease are also known and include the well-known outbreaks of multiple sclerosis, a disease of possible viral etiology, in the Faroe Islands after British troops were stationed there during the Second World War (Kurtzke and Hyllested, 1979) , and in Key West, Florida (Sheremata et al., 1985) . Many cases of HAM/TSP have been described in Japan and the Caribbean and are associated with HTLV-I infection (Gessain et al., 1985; Osame et al., 1986) . More recently, demyelination has been reported in association with the AIDS epidemic.

Throughout the process of initiation of infection, spread to the CNS, and infection of CNS cells the genetics of the host are important. Host genetic determinants of infection include the presence of appropriate cell surface receptors, and many factors present in the internal cellular environment necessary for all the stages of viral replication, assembly, and release and the immune response. Important internal cellular factors could include endosomal fusion mechanisms, intracellular pH gradients, host transcriptional factors required by the viral polymerase, and protein translation, translocation, and processing factors. These may all vary from cell to cell and in given cell types with differentiation and activation states.

Progress is being made in elucidating receptors for viruses associated with demyelinating disease. Mouse hepatitis virus binds t o a 110-kDa carcinoembryonic antigen, glycoprotein (Boyle et al., 1987; Dveksler et al., 1991) . The resistance of adult SJL mice to infection may represent a polymorphic difference between mouse strains at the site of virus binding. The receptor for HIV, CD4, is well known and the receptor for the closely related visna virus appears to be the sheep MHC class I1 molecule (Dalgleish et al., 1984; Maddon et al., 1986; Dalziel et al., 1991) . Semliki Forest virus has been reported to bind to class I MHC molecules (Helenius et al., 1978) . Theiler's virus binds to a 34-kDa membrane-associated glycoprotein (Kilpatrick and Lipton, 1991) .

The genetic control of the immune response is complex but includes among others the genes of the MHC and those encoding antibody and T cell receptor specificities. The susceptibility of the rat to MHV and the mouse to Theiler's virus-induced demyelinating disease has been linked to the induction of MHC molecules on astrocytes (Massa et al., 1987a; Rodriguez et al., 1987a) . In Theiler's virus infection, SJL mice are susceptible and C57B1/6 mice resistant and this differential susceptibility has been mapped to the H2D locus (Lipton and Melvold, 1984; Clatch et al., 1985; .

Once an infection has been initiated, in order to produce a CNS demyelinating disease the virus must usually gain access to the CNS and infect CNS cells. This was discussed in Section I and can occur by a variety of routes. Once in the CNS many viruses associated with demyelinating disease infect neurons. Strains of Theiler's, MHV, SFV, and canine distemper virus have all been reported to infect and destroy neurons. In the mouse and rabbit models, herpes simplex virus also infects neurons, although mostly those of the peripheral nerves and without producing damage. Neuronal infection by visna and HIV is rare. In adult mice, the FA and GDVII strains of Theiler's virus, high doses of MHV-4 or A59, and the L10 strain of SFV all infect and destroy CNS neurons, leading to rapid death of the animal. The brainderived WW, TO, and DA strains of Theiler's virus also infect and destroy CNS neurons, leading to a n acute paralytic disease and death of some animals. Most mice survive and develop a chronic demyelinating disease. Similarly, some mice given low doses of MHV-4 or A59 survive to develop demyelinating disease. The V5A13.1 variant of MHV infects and destroys neurons but spreads at a slower rate than the parental virus, allowing intervention of the immune response and limitation of the infection before it reaches a lethal distribution (Fazakerley et al., 1992) . The mice survive and progress to a subacute demyelinating disease. The A7(74) strain of SFV, like the L10 strain, infects neurons, but unlike the L10 strain does not destroy them (Pathak and Webb, 1978) . The infection is unproductive, and again the mice survive to develop a subacute demyelinating disease. Thus the extent of neuronal destruction and the interplay of the rate of viral spread and its control by the immune response are important in determining the early outcome of all these infections, with surviving animals in each case progressing to demyelinating disease.

Tissue culture passage of the avirulerrt TO-like strains of Theiler's virus (Lipton, 1978) results in strains that no longer produce the acute neuronal phase of the disease, but still give rise to the second phase of chronic demyelination (Lipton and Dal Canto, 197913) . These viruses infect glial cells but not neurons (Stroop et al., 1982) . Similarly, MHV-4 predominantly infects neurons, while its ts8 mutant infects predominantly glial cells (Dubois-Dalcq et al., 1981; Knobler et al., 1982) . A similar relationship is seen between MHV-DL and its variant 2.2/7.2-V-2 (Fleming et al., 19871 , and between the LlO strain of SFV and its M136 and M9 mutants (Atkins and Sheahan, 1982) . The genetic differences involved in these changes of tropism are as yet unknown. In the case of the brain-passaged, avirulent strains of Theiler's virus, the V5A13.1 variant of MHV, and the A7(74) strain of SFV, which produce acute neuronal infection followed by demyelination, it is not clear whether these viruses initially infect both neuronal and glial cells, or if glial cell infection is dependent on in uiuo generation and selection within the CNS of appropriate gliotropic variants.

Possible explanations for viral-induced demyelinating disease include, (1) direct viral destruction of oligodendrocytes, (2) direct viral lysis of persistently infected oligodendrocytes or their precursor cells in response to cell activation or differentiation, (3) infection of oligodendrocytes and immune-mediated destruction of these cells by an antiviral immune response, (4) immune-mediated destruction of oligodendrocytes as a result of virus-induced autoimmune responses, ( 5 ) destruction of oligodendrocytes by the release of toxic factors from surrounding cells as a result of an antiviral or autoimmune response, and (6) an autoimmune response resulting from a perturbation of immunological tolerance and independent of viral infection of the CNS.

An example of the first mechanism is JC papovavirus, which infects and directly destroys oligodendrocytes, leading to PML. Here the immune response is normally protective as this disease is seen only in association with immunosuppression (Walker, 1978; Johnson, 1983; Dorries et al., 1979 Dorries et al., , 1984 Aksamit et al., 1985) .

Experimental immunosuppression, depletion of lymphocyte subpopulations, and infection of athymic nulnu mice have demonstrated that the demyelination induced by the A7(74) strain of SFV is immune mediated, and that induced by the TO-like strain of Theiler's virus is at least in part immune mediated (Lipton and Dal Canto, 1977; Jagelman et al., 1978; Roos et al., 1982; Fazakerley et al., 1983; Fazakerley and Webb, 198713; Rodriguez and Quddus, 1986; Welsh et al., 1987) . The A7(74) strain of SFV rarely infects oligodendrocytes during the acute infection but by immunocytochemistry viral antigens can be detected weeks after infection in occasional astrocytes and oligodendrocytes (Khalili-Shirazi et al., 1988) . By electron microscopy, immunocytochemistry, and in situ hybridization, it has been well established that strains of Theiler's virus can infect and persist in oligodendrocytes (Brahic et al., 1981b; Stroop et al., 1981 Stroop et al., ,1982 Rodriguez et al., 1983; Rodriguez, 1985; Aubert et al., 1987) . The presence of virus in oligodendrocytes in these two systems where demyelination is immune mediated would be consistent with demyelination as a result of immune destruction of virally infected oligodendrocytes. It is also likely that demyelination in the late inflammatory lesions of canine distemper is immune mediated (Appel and Gillespie, 1972; Krakowka et al., 1973 Krakowka et al., , 1975 Appel et al., 1982) . Early lesions in this disease, often noninflammatory, probably result from direct viral effects on glial cells and may result from oligodendrocyte destruction by toxic factors released from infected astrocytes . In distemper, infected oligodendrocytes are never or rarely observed by electron microscopy (Wisniewski et al., 1972; Raine, 1976; Summers et al., 1987) . Oligodendrocytes are clearly infected by visna virus (Stowring et al., 1985) ; however, the numbers are few relative to the extent of the demyelination, and it has been suggested that immune responses may be involved in the demyelination (Nathanson et al., 1985) . The early, nondemyelinating encephalitis can be suppressed with anti-thymocyte serum (Nathanson et al., 19761 , but the role of the immune response in the later demyelinating lesions remains unclear.

In SFV, MHV-JHM, and Theiler's virus, demyelination has been shown to, or in the case of visna is likely to, involve the immune response and the virus has been demonstrated to infect oligodendrocytes. At first sight, it would appear that an immune response to viral antigens would suffice to destroy these virally infected cells and produce lesions of demyelination. However, there are several details that must not be overlooked. First, the infected oligodendrocytes would have to produce viral proteins, and for cytotoxic T lymphocytemediated destruction, peptides of these proteins would have to be presented on the cell surface in association with MHC molecules. Second, the host would require appropriate B and T cell specificities to recognize the viral protein or viral peptide-MHC complex. The situation may be complex.

As regards the expression of viral proteins during a persistent infection, this may be selective or blocked. For example, the visna virus genome can be detected by in situ hybridization in choroid plexus cells but viral protein expression is rarely observed, and it has been suggested that protein production is blocked in these cells at the level of transcription (Haase et al., 1977 (Haase et al., , 1982 . In the case of LCMV, cells acutely infected in uivo express both viral glycoprotein and nucleopro-tein. In contrast, in the persistent infection, glycoprotein expression is significantly reduced and may be undetectable, whereas nucleoprotein expression remains high (Oldstone and Buchmeier, 1982) . Expression of the hemagglutinin protein of the MBS strain of measles virus is selectively inhibited during persistence in adult hamster neurons (Swoveland and Johnson, 1989) . A similar finding has been observed in the neurons of rats persistently infected with the CAM/R40 strain of measles virus (Schneider-Schaulies et al., 1989) . In these cases, selective expression of viral proteins is associated with reduced virus production and this is linked to the differentiation state of the host cell. Neonatal or suckling animals infected with the MBS or CAM/R strains of measles virus described above succumb to a rapidly fatal encephalitis, in which all viral proteins and mature virions are produced in neurons (Johnson and Byington, 1971; Liebert and ter Meulen, 1987) . Cultured neuroblastoma cells can be productively infected with measles virus in their undifferentiated state, but virus production is significantly reduced on induction of differentiation (Miller and Carrigan, 1982) . Similarly, the A7(74) strain of SFV infects and destroys neurons in neonatal and suckling mouse brain but produces nonproductive infection in adult mouse neurons (Pathak et al., 1976; Pathak and Webb, 1988) . The same phenomenon may occur when this virus infects oligodendrocytes.

Oligodendrocytes are more difficult to study in uzuo than neurons, but a study of the JHM strain of MHV in rats suggests that virus interaction with oligodendrocytes may also depend on differentiation state. JHM virus infection of primary brain cell cultures appears to be confined to a discrete intermediate stage in oligodendrocyte differentiation between the 02A precursor cells and fully differentiated oligodendrocytes, both of which are resistant to infection (Wilson et al., 1986; Pasick and Dales, 1991) . In the case of Theiler's virus, persistently infected cells in the white matter of the spinal cord (probably oligodendrocytes) have been shown by in situ hybridization to contain low copy numbers of viral RNA. By immunoperoxidase staining no viral capsid production can be detected in these cells (Cash et al., 1985) . It would appear that RNA viruses can persist in CNS cells without expressing all their viral proteins, that is, neurons can restrict the replication of some RNA viruses. The molecular events involved remain to be elucidated.

A second feature necessary for viral-specific T cell destruction of virally infected cells is expression of MHC molecules. In mice persistently infected with LCMV, MHC class I molecules are not expressed on neurons (Mucke and Oldstone, 1992) . This may be the case for other neuronal infections. In the course of persistent LCMV infec-tion, neuronal infection may be transient and cyclical, that is, at any given time different neurons may be infected. In this scenario of persistent LCMV infection, individual neurons would first be infected from a productive, perhaps extraneural source, and then as a result of restriction of replication within the neuron, few or no mature virions would be produced, the cell would survive the infection, and any accumulated viral genetic material would be degraded (Fazakerley et al., 1991) . This and the failure of these cells to express MHC molecules and thus avoid direct cytotoxic T lymphocyte (CTL) lysis would explain why following transfer of LCMV-specific CTLs to persistently infected mice (Oldstone et al., 1986) virus is rapidly cleared from most tissues, but only slowly from the CNS.

As discussed in Section I, uninfected oligodendrocytes do not express MHC molecules. In uitro, MHC class I, but not class 11, expression can be induced by interferon y or by soluble factors released from astrocytes (Suzumura et al., 1986 (Suzumura et al., ,1988 Calder et al., 1988) . The expression of MHC molecules by infected oligodendrocytes in uzuo remains unclear. A situation similar to that described for LCMV in the neuron may exist. Failure of MHC class I expression could allow viral genetic material to persist. Occasionally, on activation or differentiation, cells could become MHC positive, resulting in immune-mediated destruction. Alternatively, change in activation or differentiation could result in complete virus replication and cell destruction.

Even if MHC expression occurs on infected CNS cells and some viral proteins are produced, responses may be limited by the availability of a T cell epitope. Cytotoxic T lymphocytes may respond to only one or two epitopes on a glycoprotein and these differ according t o the MHC type. It has been estimated that for a single MHC molecule there is an average of only one CTL epitope per 1500 amino acids of virus protein (Whitton and Oldstone, 1989) . For example, mice of the H2b haplotype produce a CTL response to the glycoprotein of lymphocytic choriomeningitis virus, but no T cell epitopes are recognized on this molecule by H2d mice (Whitton et al., 1988) . Selective protein expression in persistently infected cells may therefore significantly decrease the chances of a CTL immune response to these cells. Although apparently straightforward because both antibody and T cell reactivity to viral antigens have been demonstrated in experimental and human demyelinating diseases, viral-specific, MHC-restricted, immune-mediated destruction of virally infected oligodendrocytes remains to be proved as a mechanism of demyelination.

There is no a priori reason to invoke autoimmune mechanisms of demyelination in viral-associated demyelinating disease. Nevertheless, autoreactivity has now been widely observed. Antibody and T cell responses to myelin antigens have been reported for rats infected with MHV or measles virus, mice infected with Theiler's virus or SFV, dogs infected with canine distemper, and cases of human measles encephalomyelitis (Krakowka et al., 1973; Vandevelde et al., 1982a; Cerruti-Sola et al., 1983; Watanabe et al., 1983; Johnson et al., 1984; Rauch et al., 1987; Welsh et al., 1987; Mokhtarian and Swoveland, 1987; Liebert et al., 1988) . The level of these responses sometimes correlates with the extent of the demyelinating disease, as observed for myelin antibody titers in some dogs with distemper (Krakowka et al., 1973; Cerruti-Sola et al., 1983) and in some mice infected with Theiler's (DA) virus (Rauch et al., 1987) . In other cases no correlation is apparent, because high titers of anti-myelin antibody are also observed in dogs with distemper that have no lesions of demyelination , and SJL mice infected with Theiler's virus can develop lesions of demyelination in the absence of immune responses to MBP or PLP .

It is not yet clear whether CNS autoimmune responses in viralassociated demyelinating disease are important in the pathogenesis or are epiphenomena. The transfer of inflammatory CNS disease to uninfected animals with immune cells, as has been reported with MBPspecific T cells from JHM-infected Lewis rats t o naive uninfected rats (Watanabe et al., 19831 , must be interpreted with caution because it is not clear that the recipients developed lesions of demyelination. Central nervous system perivenular inflammation as a result of the transfer of MBP-specific T cells is to be expected. The subacute demyelinating disease seen in Lewis rats infected with this virus is likely to result from a more complex pathogenesis. The role of immune responses to viral antigens, antibody to autoantigens, and their synergistic effects with this MBP-specific T cell response must be considered. Transfer of MBP-specific T cells to naive rats usually results in an inflammatory CNS disease with minimal demyelination. Lesions of demyelination can be significantly increased by the additional transfer of anti-oligodendrocyte antibody . As discussed in Section I, anti-oligodendrocyte antibodies, and particularly those to the glycolipid galactocerebroside, have been previously determined to produce demyelination. In this context it has been proposed that glycolipid in the envelope of viruses budding from oligodendrocytes may be immunogenic and initiate immune responses to glycolipids such as galactocerebroside (Webb and Fazakerley, 1984) .

Demyelination could depend on both generation of T cell-mediated inflammatory reactions, to either viral or CNS antigens and production, perhaps locally by plasma cells recruited into these lesions, of anti-oligodendrocyte antibodies.

Autoreactivity to CNS antigens could result from a breaking of tolerance in response t o the release of large amount of CNS antigens (e.g., MBP) during the acute, highly destructive phase of many of these CNS diseases. The levels of MBP in the cerebrospinal fluid of dogs with distemper is related to the severity of the disease (Summers et al., 1987) .

Another mechanism for the viral induction of autoimmune responses is cross-reactivity between viral and host cell proteins, termed molecular mimicry (Notkins et al., 1984; Oldstone, 1987) . The polymerase protein of hepatitis B virus contains a motif of six amino acids also found in the rabbit encephalitogenic site of MBP. A peptide containing these six amino acids and the flanking amino acids in the hepatitis B sequence when inoculated into rabbits produces CNS inflammation, and antibody and T cell responses that cross-react with MBP (Fujinami and Oldstone, 1985) . However, this appears to be of little relevance, because with the exception of a case of peripheral neuropathy involving demyelination (Tsukada et al., 1987) in which cross-reactivity to CNS MBP is not relevant, hepatitis B virus infection has not been associated with lesions of demyelination. Sequence similarities of various lengths and numbers of identical residues have now been reported for CNS antigens and many viruses (Jahnke et al., 1985; Shaw et al., 1986) . At present, the significance of these to CNS disease remains uncertain.

Much of the impetus for studying virus-associated demyelination has derived from the view that MS is likely to have an infectious etiology. Demyelination in this disease could occur by any of the mechanisms observed in the experimental animal models following infection by an as yet unidentified virus. Perhaps more likely is that demyelination in MS can be initiated by infection with one of several viruses, possibly even acting by different mechanisms to produce lesions of CNS demyelination. After all, MHV, SFV, and Theiler's virus all produce inflammatory, demyelinating lesions in the mouse CNS that are histopathologically difficult to tell apart.

Whatever the mechanism of demyelination in MS, little or no significant remyelination occurs. This is in contrast to the situation in many of the animal models in which extensive remyelination is often observed. Understanding the molecular events that control remyelination should be a major component of future research in virus-induced demyelinating disease.

This work was supported by a Research Fellowship from the British Multiple Sclerosis Society to J.K.F. and National Institutes of Health Grants A1 25913, NS 12428, and NS 22347 to M.J.B. We are grateful to Dr. S. Perlman for review of the manuscript and to J. Johnston for manuscript preparation.

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Isolation of canine distemper virus from dogs with chronic neurological disease

Early loss of astrocytes in herpes simplex virus-induced central nervous system demyelination

The pathogenesis of avirulent Semliki Forest virus infections in athymic nude mice

Sequence homology between certain viral proteins and proteins related to encephalomyelitis and neuritis

Transferrin receptor on endothelium of brain capillaries

Subacute sclerosing panencephalitis-immunoultrastructural localization of measlesvirus antigen

Changes in fast axonal transport of glycoproteins in optic nerves of mice infected with Semliki Forest virus

Evidence for a T-cell related factor as the cause of demyelination in mice following Semliki Forest virus infection

Subacute sclerosing panencephalitis (SSPE) agent in hamsters. I. Acute giant cell encephalitis in newborn animals

Immune mediated syndromes of the nervous system related to virus infections

Experimental rabies. Studies of cellular vulnerability and patho-Pathol

genesis using fluorescent antibody staining

Viral Infections of the Nervous System

Evidence for polyomaviruses in human neurological diseases

Measles encephalomyelitis-clinical and immunologic studies

The neurobiology of human immunodeficiency virus infections

Viral persistence in neurons explained by lack of major histocompatibility class I expression

Expression of viral and myelin gene transcripts in a murine CNS demyelinating disease caused by a coronavirus

Differential modulation of MHC class I antigen expression on mouse brain endothelial cells by MHV-4 infection

Mouse hepatitis virus (MHV-4, JHM) blocks gamma interferon-induced major histocompatibility complex class I1 antigen expression on murine cerebral endothelial cells

Multifocal CNS demyelination following peripheral inoculation with herpes simplex virus type 1

The significance of failure to isolate infectious viruses in cases of subacute sclerosing panencephalitis

Demyelination induced in mice by avirulent Semliki Forest virus. 11. An ultrastructural study of focal demyelination in the brain

Immunological relationship between a demyelinating RNA enveloped budding virus (Semliki Forest) and brain glycolipids

Immunocytochemical evidence for Semliki Forest virus antigen persistence in mouse brain

Predominant binding of Theiler's viruses to a 34-kilodalton receptor protein on susceptible cell lines

Mouse hepatitis virus type-4 (JHM strain)-induced fatal central nervous system disease. I. Genetic control and the murine neuron as the susceptible site of disease

Selected mutants of mouse hepatitis virus type 4 (JHM strain) induce different CNS diseases. Pathobiology of disease induced by wild type and mutants ts8 and ts15 in BALB/c and SJL/J mice

encephalomyelitis: The balance between encephalitogenic T lymphocytes and demyelinating antibodies determines size and structure of demyelinated lesions

Demyelinative myelopathy in mice induced by the DA virus

Virological aspects of measles virus induced encephalomyelitis in Lewis and BN rats

Restricted expression of measles virus proteins in brains from cases of subacute sclerosing panencephalitis

Induction of autoimmune reactions to myelin basic protein in measles virus encephalitis in Lewis rats

Antibody induced restriction of viral gene expression in measles encephalitis in rats

Characterization of measles virus-induced cellular autoimmune reactions against myelin basic protein in Lewis rats

Absence of M protein in a cell-associated subacute sclerosing panencephalitis virus

Cytotoxic T cells isolated from the central nervous system of mice infected with Theiler's virus

Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelinioligodendrocyte glycoprotein

Inflammatory neuropathy in homosexual men with lymphadenopathy

Viral infection of neurons can depress neurotransmitter mRNA levels without histologic injury

Theiler's virus infection in mice. An unusual biphasic disease process leading to demyelination

Characterization of the TO strains of Theiler's mouse encephalomyelitis viruses

Contrasting effects of immunosuppression on Theiler's virus infection in mice

Susceptibility of inbred mice to chronic central nervous system infection by Theiler's murine encephalomyelitis virus

The TO strains of Theiler's viruses cause "slow virus-like" infections in mice

Central nervous system immunity in mice infected with Theiler's virus. I. Local neutralizing antibody response

Genetic analysis of susceptibility to Theiler's virus-induced demyelinating disease in mice

Theiler's virus antigen detected in mouse spinal cord 24 years after infection

The 5' noncoding sequences from a less virulent Theiler's virus dramatically attenuate GDVII neurovirulence

Cell-mediated immunity rof myelin basic protein in acute disseminated encephalomyelitis

Distribution of Theiler's virus in the CNS of athymic nude mice: Effect of varying the route of inoculation

Central nervous system demyelination and remyelination in the mouse: An ultrastructural study of cuprizone toxicity

Antigenic drift in visna: Virus variation during long-term infection of Icelandic sheep

Primary structure of the glycoprotein E2 of mouse hepatitis virus strain A59 and identification of the trypsin cleavage site

Histopathological and enzyme histochemical changes in experimental Semliki Forest virus infection in mice and their relevance to scrapie

The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and in the brain

Antigen presentation in brain: MHC induction on brain endothelium and astrocytes compared

Acute dissemination encephalomyelitis") in smallpox

Spinal cord and optic nerve demyelination in experimental herpes simplex virus type 2 infection

The nervous system in genital herpes simplex virus type 2 infections in mice. Lethal panmyelitis or nonlethal demyelinative myelitis or meningitis

Cerebrospinal fluid immunoglobulins in sheep with visna, a slow virus infection of the central nervous system

Viral particles induce Ia antigen expression on astrocytes

Inducibility of Ia antigen on astrocytes by murine coronavirus JHM is rat strain dependent

Tumor necrosis factor amplifies measles virus-mediated Ia induction on astrocytes

An outbreak of human Semliki Forest virus infections in Central African Republic. A m

An attempt to differentiate further between microglia and fluorescent granular perithelial (FGP) cells by their capacity to incorporate exogenous protein

Immunochemical analysis of the rat central nervous system during experimental allergic encepha

lomyelitis with special reference to Ia-positive cells with dendritic morphology

Detection of HLA-DR on microglia in the human brain is a function of both clinical and technical factors. A m

Molecular cloning of the complete genome of Theiler's virus, strain DA, and production of infectious transcripts

Presentation of myelin basic protein by murine cerebral vascular endothelial cells

Experimental canine distemper virus-induced demyelination

The encephalitogenic activity and myelin basic protein content of isolated oligodendroglia

The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1

Variations in genetic control of susceptibility to Theiler's rnurine encephalomyelitis virus (TMEVIinduced demyelinating disease

Identification of a locus on mouse chromosome 3 involved in differential susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease

Interleukin 1 and tumor necrosis factor alpha can be induced from mononuclear phagocytes by human immunodeficiency virus type-1 binding to the CD4 receptor

Reversible repression and activation of measles virus infection in neural cells

Prognosis of neurologic illness following vaccination against smallpox

Parainfectious encephalomyelitis and related syndromes

Class 11-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. 111. Failure of neuroantigen-specific immune tolerance to affect the clinical course of demyelination

Viral expression in experimental canine distemper demyelinating encephalitis

Predisposition to EAE induction in resistant mice by prior infection with Semliki Forest virus

Tropical spastic paraparesis: a model of virus-induced, cytotoxic T-cell-mediated demyelination

Infection of cultured murine brain cells by Semliki Forest virus: Effects of interferon-alpha, beta on viral replication, viral antigen display, major histocompatibility antigen display and lysis by cytotoxic T lymphocytes

Characterization of coronavirus JHM variants isolated from Wistar Furth rats with a viral induced demyelinating disease

The expression of major histocompatibility complex (MHC) class I antigens in the brain differs markedly in acute and persistent infections with lymphocytic choriomeningitis virus (LCMV)

Rabies pathogenesis. Brief review

Eastern equine encephalitis virus infection: Electron microscopic studies of mouse central nervous system

Lentiviral diseases of sheep and goats: chronic pneumonia leukoencephalomyelitis and arthritis

Slow virus replication: The role of macrophages in the persistence and expression of visna viruses of sheep and goats

Lentivirus-host interactions: lessons from visna and caprine arthritis-encephalitis viruses

Virological and pathological processes involved in Theiler's virus infection of the central nervous system

Epidemiology of multiple sclerosis, critique of the evidence for a viral etiology. A m

Pathogenesis of visna. 11. Effect of immunosuppression upon early central nervous system lesions

Pathogenesis of visna. IV. Spinal fluid studies

Experimental visna in Icelandic sheep: The prototype lentiviral infection

The AIDS dementia complex. I. Clinical features

HIV and HCMV coinfect brain cells in patients with AIDS

Identification of a cDNA coding for a fifth form of myelin basic protein in mouse

Subacute encephalitis in acquired immune deficiency syndrome: A postmortem study

West Nile virus infection in mice following exposure to a viral aerosol

Measles virus matrix protein detected by immune fluorescence with monoclonal antibodies in the brain of patients with subacute sclerosing panencephalitis

Concepts in Viral Pathogenesis

Japanese encephalitis virus neurotropism is dependent on the degree of neuronal maturity

Molecular cloning and sequence determination of DA strain of Theiler's murine encephalomyelitis viruses

Molecular mimicry and autoimmune disease

Restricted expression of viral glycoprotein in cells of persistently infected mice

Cytoimmunotherapy for persistent virus infection reveals a unique clearance pattern from the central nervous system

Histopathology of CNS of mice infected with virus of Theiler's disease (spontaneous encephalomyelitis)

Ovine progressive pneumonia: Pathologic and virologic studies on the naturally occurring disease. A m

Subacute sclerosing panencephalitis associated glomerulopathy

T-cell requirement for experimental allergic encephalomyelitis induction in the rat

HTLV-I associated myelopathy: A new clinical entity

Theiler's virus genome is closely related to that of encephalomyocarditis virus, the prototype cardiovirus

Molecular cloning of the gene encoding the putative polymerase of mouse hepatitis coronavirus, strain A59

Cultivation of papovalike virus from human brain with progressive multifocal leukoencephalopathy

Differential nerooncogenicity of strains of JC virus, a human polyoma virus, in newborn Syrian hamsters

Cyclosporine penetration into the anterior chamber and cerebrospinal fluid

Immune responses to central nervous system antigens in experimental allergic encephalomyelitis and visna

Sequence analysis reveals extensive polymorphism and evidence of deletions within the E2 glycoprotein gene of several strains of murine hepatitis virus

Peripheral neuropathies associated with human immunodeficiency virus infection

Virus titres and persistently raised white cell counts in cerebrospinal fluid in mice after peripheral infection with demyelinating Semliki Forest virus

Blood brain barrier disturbance and immunoglobulin G levels in the cerebrospinal fluid of the mouse following peripheral infection with the demyelinating strain of Semliki Forest virus

Infection by coronavirus JHM of rat neurons and oligodendrocyte-type-2 astrocyte lineage cells during distinct developmental stages

Transfer of allergic encephalomyelitis in rats by means of lymph node cells

Possible mechanisms for the transport of Semliki Forest virus into and with mouse brain: An electron microscopic study

An electron-microscopic study of avirulent and virulent Semliki forest virus in the brains of different ages of mice

The entry and the transport of arboviruses into and throughout mouse brain: An electron-microscopic study

Effect of myocrisin (sodium auro-thio-malate) on the morphogenesis of avirulent Semliki Forest virus in mouse brain: An electron microscopical study

An electron microscopical study of the replication of avirulent Semliki Forest virus in the retina of mice

An electron-microscopic study of the development of virulent and avirulent strains of Semliki Forest virus in mouse brain

The identification and role of cells involved in CNS demyelination in mice after Semliki Forest virus infection: An ultrastructural study. Prog

Isolation of measles virus from cell cultures of brain from a patient with subacute sclerosing panencephalitis

Biology of Marek's disease virus and the herpesvirus of turkeys

Theiler's virus infection induces a specific cytotoxic T lymphocyte response

Late onset, symptomatic, demyelinating encephalomyelitis in mice infected with MHV-JHM in the presence of maternal antibody

Spread of a neurotropic murine coronavirus into the CNS via the trigeminal and olfactory nerves

The formation and fate of virus antigenantibody complexes

Macrophages and microglia in the nervous system

Increase in axonal transport in demyelinating optic nerve fibers in mice infected with Semliki Forest virus

Varicella and acute cerebellar ataxia

Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome

Pathogenesis of visna. I. Sequential virologic, serologic, and pathologic studies

Immunopathogenesis of visna. A slow virus disease of the central nervous system

Analysis of the complete nucleotide sequence of the picornavirus Theiler's murine encephalomyelitis virus indicates that it is closely related to cardioviruses

Insights into Theiler's virus neurovirulence based on a genomic comparison of the neurovirulent GDVII and less virulent BeAn strains

The isolation ofantisera to neuronal and oligodendroglial surface components

Electron-microscopic appearance of the DA virus, a demyelinating murine virus

Antigen presentation in brain: brain endothelial cells are poor stimulators of T-cell proliferation

Progress in the control of Mareks disease. A m

Infection pattern in mice of a n avirulent and virulent strain of Semliki Forest virus

Nucleotide sequence analysis of SA-OMVV a visna related ovine lentivirus: Phylogenetic history of lentiviruses

Herpes simplex virus in mice: Electron microscopy of neural spread

Cellular immunity in chronic Theiler's virus central nervous system infection

A glial progenitor cell that develops in vitro into an astrocyte or a n oligodendrocyte depending on culture medium

Two types of astrocytes in cultures of developing rat white matter: Differences in morphology, surface gangliosides, and growth characteristics

Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture

On the development of CNS lesions in natural canine distemper encephalomyelitis

Studies on the encephalitogenic effects of purified preparations of human and bovine oligodendrocytes

Interferon-beta specifically inhibits interferon-gamma induced class I1 major histocompatibility complex gene transcription in a human astrocytoma cell line

Chronic Theiler's virus infection in mice: appearance of myelin basic protein in the cerebrospinal fluid and serum antibody directed against MBP

Intra blood-brain barrier synthesis of HTLV-I11 specific IgG in patients with neurologic symptoms associated with AIDS or AIDS-related complex

Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes

MRC 0x43: A monoclonal antibody which reacts with all vascular endothelium in the rat except that of brain capillaries

Virus-induced demyelination in mice

Effect of cyclosporin A, silica quartz dust, and protease inhibitors on virus-induced demyelination

Pathogenesis of early and late disease in mice infected with Theiler's virus, using intratypic recombinant GDVIIiDA viruses

Successful therapy of Theiler's virus-induced demyelination (DA strain) with monoclonal anti-Lyt-2 antibody

Susceptibility to Theiler's virusinduced demyelination. Mapping of the gene within the H-2D region

Immune response gene products (Ia antigens) on glial and endothelial cells in virus-induced demyelination

Theiler's murine encephalomyelitis: A model of demyelination and persistence of virus

Role of T cells in resistance to Theiler's virus infection

Biochemical analysis of DA strain of Theiler's murine encephalomyelitis virus obtained directly from acutely infected mouse brain

Immunologic and virologic studies of measles inclusion body encephalitis in an immunosuppressed host: The relationship to subacute sclerosing panencephalitis

The effect of short-term and chronic immunosuppression on Theiler's virus demyelination

Infectious cDNA clones of the DA strain of Theiler's murine encephalomyelitis virus

Mechanism of Theiler's virusinduced demyelination in nude mice

Sindbis virus mutations which coordinately affect glycoprotein processing, penetration, and virulence in mice

Antiserum-mediated demyelination in vivo: Observations after intraneural injection of experimental allergic encephalomyelitis (EAE) and neuritis (EAN) serum

Demyelinating anti-galactocerebroside antibodies in EAN and EAE

Anti-oligodendrocyte serum demyelinates cultured CNS tissue

In vivo demyelination induced by serum from animals with experimental allergic encephalomyelitis (EAE)

Peripheral nerve demyelination induced by intraneural injection of experimental allergic encephalomyelitis serum

Ia expression in chronic relapsing experimental allergic encephalomyelitis induced by long-term cultured T cell lines in mice

The nucleotide sequence and transcriptional analysis of molecular clones of CAEV which generate infectious virus

Nucleotide sequence of EV1, a British isolate of maedi-visna virus

Cell type-specific surface antigens in the mammalian nervous system

Nucleotide sequence of the gene encoding the surface projection glycoprotein of coronavirus MHV-JHM

Restriction of measles virus gene expression in acute and subacute encephalitis of Lewis rats

Restricted expression of measles virus in primary rat astroglial cells

Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States. A m

Glial marker enzymes

Meningoencephalomyelitis with epidemic parotitis

Ross River virus-induced demyelination: I. Pathogenesis and histopathology

Ross River virus-induced demyelination: 11. Ultrastructural studies

Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system

Rabies virulence: Effect on pathogenicity and sequence characterization of rabies virus mutations affecting antigenic site I11 of the glycoprotein

Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro

Search for virus nucleic acid sequences in postmortem human brain tissue using in situ hybridization technology with cloned probes: Some solutions and results in progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis tissue

Multinucleated giant cells and HTLV-I11 in AIDS encephalopathy

HTLV-111 infection in brains of children and adults with

Analogous amino acid sequences in myelin proteolipid and viral proteins

Demyelination in mice from infection with a mutant of Semliki Forest virus

Oligodendrocyte infection and demyelination produced in mice by the M9 mutant of Semliki Forest virus

Unusual occurrence on a tropical island of multiple sclerosis

The biology of coronaviruses

Observations on three slow infections of sheep, maedi, paratuberculosis, and rida, a chronic encephalitis of sheep, with general remarks on infections which develop slowly and some of their special characteristics

Cu1tivationofvisna.virus in tissue culture

Pathology ofvisna. Transmissible demyelinating disease in sheep in Iceland

The early region of human papovavirus J C induces dysmyelination in transgenic mice

The mutation rate and variability of eukaryotic viruses: An analytical review

Neurological complications of acquired immune deficiency syndrome: Analysis of 50 patients

The immunopathology of experimental allergic encephalomyelitis. 11. Endothelial cell Ia increases prior to inflammatory cell infiltration

Intracellular adhesion molecule-1 (ICAM-1) in cellular immune reactions in the human central nervous system

Monoclonal antibodies (01 to 04) to oligodendrocyte cell surfaces: an immunocytochemical study in the central nervous system

Nucleotide sequence of visna lentivirus: Relationship to the AIDS virus

In vivo and in vitro models of demyelinating disease: Endogenous factors influencing demyelinating disease caused by mouse hepatitis virus in rats and mice

In vivo and in vitro models of demyelinating disease. XVII. The infectious process in athymic rats inoculated with JHM virus

Subacute sclerosing panencephalitis: An immune complex disease

Coronaviruses: Structure and genome expression

Recent morphological studies of toxic neuropathy

The neurology of Jennerian vaccination. A clinical account of the neurological complications which occurred during the smallpox epidemic in South Wales in 1962

Hemagglutinin variants of reovirus type 3 have altered central nervous system tropism

In situ amplification of visna virus DNA in tissue sections reveals a reservoir of latently infected cells

Isolation of replication-competent molecular clones of visna virus

In vivo effects of coronavirus-specific T cell clones: DTH inducer cells prevent a lethal infection but do not inhibit virus replication

Detection of visna virus antigens and RNA in glial cells in foci of demyelination

Response of endogenous glial cells to motor neuron degeneration induced by toxic ricin

Detection ofTheiler's virus RNA in mouse central nervous system by in situ hybridization

Detection of tissue culture-adapted Theiler's virus RNA in spinal cord white matter cells throughout infection

Localization of herpes simplex virus in the trigeminal and olfactory systems of the mouse central nervous system during acute and latent infections by in situ hybridization

Brain lysosomal glycosidase activity in immunosuppressed mice infected with avirulent Semliki Forest virus

The effect of mouse strain on the pathogenesis of the encephalitis and demyelination induced by avirulent Semliki Forest virus infections

Demyelination in canine distemper encephalomyelitis: an ultrastructural analysis

Possible initiation of viral encephalomyelitis in dogs by migrating lymphocytes infected with distemper

Demyelinating canine distemper encephalomyelitis: Measurement of myelin basic protein in cerebrospinal fluid

Coronavirus infection induces H-2 antigen expression on oligodendrocytes and astrocytes

Induction of glial cell MHC antigen expression in neurotropic coronavirus infections. Characterization of the H-%inducing soluble factor elaborated by infected brain cells

Host age and cell type influence measles virus protein expression in the central nervous system

Characterization of a variant virus selected in rat brains after infection by coronavirus mouse hepatitis virus JHM

Characterization of a variant virus isolated from neural cell culture after infection of mouse coronavirus JHM

Molecular cloning of the complete genome of Theiler's virus, strain GDVII, and production of infectious transcripts

Determinants of persistence and demyelination of the DA strain of Theiler's virus are found only in the VP1 gene

The relationship between axonal transport of protein and demyelination in the optic nerves of mice infected with Semliki Forest virus

Spontaneous encephalomyelitis of mice-a new virus disease

Acute disseminated encephalitis following immunization with homologous brain extracts: Studies on role of circulating antibody in production of condition in dogs

A spontaneous epizootic of mouse encephalomyelitis

The Molecular Biology of Tumor Viruses

The relationship of astrocytes and macrophages to CNS demyelination after experimental herpes simplex virus infection

Schwann cell remyelination in experimental herpes simplex encephalitis at the trigeminal root entry zone

Comparative vulnerability of peripheral and central nervous tissue to herpes simplex virus

Central nervous system susceptibility to herpes simplex infection

Peripheral nervous system demyelination with herpes simplex virus

The neuropathology of progressive rubella panencephalitis of late onset

Multiple sclerosis: evidence for antigen presentation in situ by endothelial cells and astrocytes

Physiological deficits in the visual system of mice infected with Semliki Forest virus and their correlation with those seen in patients with demyelinating disease

Cells positive for the 0 4 surface antigen isolated by cell sorting are able to differentiate into astrocytes or oligodendrocytes

Demyelinating neuropathy associated with hepatitis B virus infection: Detection of immune complexes composed of hepatitis B virus surface antigen

Distinct pathways of viral spread in the host determined by reovirus S1 gene segment

Identification of a putative alphavirus receptor on mouse neural cells

Immunological and pathological findings in demyelinating encephalitis associated with canine distemper virus infection

Demyelination in experimental canine distemper virus infection: Immunological, pathologic, and immunohistological studies

Glial proteins in canine distemper virus-induced demyelination

Spread and distribution of viral antigen in nervous canine distemper

Studies on the intrathecal humoral immune response in canine distemper encephalitis

The distribution of Ia antigens in the lesions of rat acute experimental allergic encephalomyelitis

Precursor polypeptides to structural proteins of visna virus

Envelope structure of Semliki Forest virus reconstructed from cryo-electron micrographs

Tumor necrosis factor (alpha, beta) induced by HIV-1 in peripheral blood mononuclear cells potentiate virus replication

Progressive multifocal leukoencephalopathy: An opportunistic viral infection of the central nervous system

Demyelination induced by murine hepatitis virus JHM strain (MHV-4) is immunologically mediated

Adoptive transfer of EAE-like lesions from rats with coronavirus-induced demyelinating encephalomyelitis

Comparative analysis of coronavirus JHM-induced demyelinating encephalomyelitis in Lewis and Brown Norway rats

Can viral envelope glycolipids produce autoimmunity, with reference to the CNS and multiple sclerosis?

Semliki Forest virus infections in mice as a model for studying acute and chronic central nervous system virus infections in man

Immunological reaction of the demyelinating Semliki Forest virus with immune serum to glycolipids and its possible importance to central nervous system viral auto-immune disease

Differences between the intracellular polypeptides of measles and subacute sclerosing panencephalitis virus

Neurovirulence of murine coronavirus JHM temperature-sensitive mutants in rats

Coronavirus infection of rats: A model for virus induced demyelinating disease associated with autoimmunity

The peplomer protein E2 of coronavirus JHM as a determinant of neurovirulence: Definition of critical epitopes by variant analysis

Pathogenesis of demyelination induced by a mouse hepatitis virus (JHM virus)

Isolation of virus related to SV40 from patients with progressive multifocal leukoencephalopathy

Immune reactivity in the nervous system: Modulation of T-lymphocyte activation by glial cells

The effect of L3T4 T cell depletion on the pathogenesis of Theiler's murine encephalomyelitis virus infection in CBA mice

Theiler's virus: An experimental model of virus-induced demyelination

Antigen recognition by cytotoxic T cells. I n "Concepts in Viral Pathogenesis 111

Analyses of the cytotoxic T lymphocyte responses to glycoproteins and nucleoprotein components of lymphocytic choriomeningitis virus

Recovery of viral agents from the central nervous system of cats

Role of human immunodeficiency virus and cytomegalovirus in AIDS encephalitis. A m

Human immunodeficiency virus: Infection of the nervous system

Human immunodeficiency virus (HIV) and J C virus in acquired immune deficiency syndrome (AIDS) patients with progressive multifocal leukoencephalopathy

Sernliki Forest virus: Cause of a fatal case of human encephalitis

The generation of neurons and oligodendrocytes from a common precursor cell

Purification of the 110-kilodalton glycoprotein receptor for mouse hepatitis virus (MHVbA59 from mouse liver and identification of a nonfunctional homologous protein in MHV-resistant SJLiJ mice

Characterization ofbraininfiltrating mononuclear cells during infection with mouse hepatitis virus strain JHM

In vivo and in vitro models of demyelinating diseases. XV. Differentiation influences the regulation of coronavirus infection in primary explants of mouse CNS

Observation on viral demyelinating encephalomyelitis

Persistence of neuroadapted mumps virus in brains of newborn hamsters after intraperitoneal inoculation

Tumour necrosis factors alpha and beta inhibit virus replication and synergize with interferons

Inducible expression of H-2 and Ia antigens on brain cells

Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: Evidence of a role for microglia in cytokine production

Investigations of reasons for the avirulence of the A7 strain of Semliki Forest virus in adult mice

Growth of the WW strain of Theiler virus in mouse central nervous system organotypic culture

The relationship between viral RNA, myelin-specific mRNAs, and demyelination in central nervous system disease during Theiler's virus infection

Protection of mice from a lethal coronavirus infection in the central nervous system by adoptive transfer of virus-specific T cell clones

Sialosylgalactosyl ceramid as a specific marker for myelin and oligodendroglia perikaria

A neutralization-resistant Theiler's virus variant produces an altered disease pattern in the mouse central nervous system

Secondary degeneration of oligodendrocytes in canine distemper virus infection in vitro

Direct evidence of a role for amino acid 101 of VP-1 in central nervous system disease in Theiler's murine encephalomyelitis virus infection

Association of papova-virions with a human demyelinating disease (progressive multifocal leukoencephalopathy)