key: cord-0008869-62riomdu
authors: Fenner, Frank
title: The nature and classification of viruses of man
date: 2002-11-14
journal: Pharmacol Ther
DOI: 10.1016/0163-7258(79)90014-7
sha: 328d8876d98f186e74fdaceb686ff200b44eec1c
doc_id: 8869
cord_uid: 62riomdu

nan

Virology began as a branch of pathology. At the end of the nineteenth century, when the microbial etiology of many infectious diseases had been established, pathologists recognized that there were a number of common infectious diseases of man and his domesticated animals for which neither a bacterium nor a protozoan could be incriminated as the causal agent. In 1898, Loeflter and Frosch demonstrated that foot-and-mouth disease could be transferred from one animal to another by material which could pass through a filter that retained the smallest bacteria. Following this discovery such diseases were tentatively ascribed to what were first called 'ultramicroscopic filterable viruses ', then 'ultrafilterable viruses', and, ultimately, just 'viruses' . The word 'virus' itself, originally meaning a disease-producing poison, was appropriated to this particular class of agents because of the currency that Jenner had given to the term in describing cowpox and smallpox viruses a hundred years earlier. Fenner and White (1976) .

It is impossible to define viruses satisfactorily in a sentence or even a paragraph, bearing in mind both their intracellular states and the extracellular particles or virions. Virions consist of a genome of either DNA or RNA enclosed within a protective coat of protein molecules, some of which may be associated with carbohydrates or lipids of cellular origin. In the vegetative state and as 'provirus', viruses may be reduced to their constituent genomes, and the simplest 'viruses' may be transmitted from one host to another as naked molecules of nucleic acid, possibly associated with certain cellular components. At the other extreme, the largest animal viruses, the poxviruses and the retroviruses, are relatively complex.

Viruses parasitize every kind of organism; possibly, indeed, every individual organism, prokaryote and eukaryote, is infected with one or more viruses. For our purposes we need consider only the viruses of vertebrate animals--mainly those of man, but also some viruses that infect domestic or experimental animals and are important in experimental virology, including viral chemotherapy.

The simpler viruses consist solely of nucleic acid and a few virus-specified polypeptides. More complex viruses usually also contain lipids and carbohydrates; in the great majority of viral families these chemical components are not specified by the viral genome but are derived from the cells in which the viruses multiply. In exceptional situations, cellular nucleic acids or polypeptides may be incorporated in viral particles.

Viruses, unlike microorganisms, contain only a single species of nucleic acid, which may be DNA or RNA. In different families of viruses the nucleic acid is single-or double-stranded, a single molecule or several, and if a single molecule either linear or cyclic. As yet, no animal viral nucleic acid has been found to be methylated, or to contain novel bases of the type encountered in bacterial viruses or mammalian transfer RNA's, but some virions contain oligonucleotides rich in adenylate, of unknown function. The base composition of DNA from animal viruses covers a far wider range than that of the vertebrates, for the guanine plus cytosine (G + C) content of different viruses varies from 35 to 74 per cent, compared with 40 to 44 per cent for all chordates. Indeed, the G +C content of the DNA of viruses of one family (Herpetoviridae) ranges from 46 to 74 per cent.

The molecular weights of the DNA's of different animal viruses vary from just over 1 to about 150 × 106 daltons; the range of molecular weights of viral RNA's is much less~ from just over 2 to about 15 × 106 daltons. The nucleic acid can be extracted from viral particles with detergents or phenol. The released molecules are often easily degraded, but the isolated nucleic acid of viruses belonging to certain families is infectious. In other cases, the isolated nucleic acid is not infectious even though it contains all the necessary genetic information, for its transcription depends upon a virion-associated transcriptase without which multiplication cannot proceed.

The genomes of all DNA viruses consist of a single molecule of nucleic acid, but the genomes of many RNA viruses consist of several different molecules, which are probably loosely linked together in the virion. In viruses whose genome consists of single-stranded nucleic acid, the viral nucleic acid is either the 'positive' strand (in RNA viruses, equivalent to messenger RNA) or the 'negative ' (complementary) strand. Preparations of some Parvoviridae, which have genomes of single-stranded DNA, consist of particles that contain either the positive or the complementary strand.

Viral preparations often contain some particles with an atypical content of nucleic acid. Host-cell DNA is found in some papovaviruses, and what appear to be cellular ribosomes in some arenaviruses. Several copies of the complete viral genome may be enclosed within a single particle (as in paramyxoviruses) or viral particles may be formed that contain no nucleic acid ('empty' particles) or that have an incomplete genome, lacking part of the nucleic acid that is needed for infectivity.

Terminal redundancy occurs in the DNA of some vertebrate viruses, but most sequences are unique. The largest viral genomes contain several hundred genes, while the smallest carry only sufficient information to code for about half a dozen proteins, most of which are structural proteins of the virion.

The major constituent of the virion is protein, whose primary role is to provide the viral nucleic acid with a protective coat. The protein shells of the simpler viruses consist of repeating protein subunits. Sometimes the capsid protein consists of only one sort of polypeptide; more commonly there are two or three different polypeptides in the protein shell. Often certain of these surface polypeptides have a special affinity for complementary 'receptors' present on the surface of susceptible cells. They also contain the antigenic determinants that are responsible for the production of protective antibodies by the infected animal.

Viral polypeptides are quite large, with molecular weights in the range 10,000-150,000 daltons. The smaller polypeptides are often, but not always, internal; the larger ones often, but not always, external. There are no distinctive features about the amino acid composition of the structural polypeptides of the virion, except that those intimately associated with viral nucleic acid in the 'core' of some icosahedral viruses are often relatively rich in arginine.

Viral envelopes usually originate from the cellular plasma membrane from which the original cellular proteins have been totally displaced by viral peplomers and a viral 'membrane protein' (see Fig. 1 ). The peplomers consist of repeating units of one or two glycoproteins, the polypeptide moiety of which is virus-specified while the carbohydrate is added by cellular transferases. In many enveloped viruses, the inside of the viral envelope is lined by a viral protein called the membrane or matrix protein.

Not all structural viral proteins are primary gene products, since in viruses of several families the viral mRNA is translated into a large polypeptide that is en-zymaticaUy cleaved to yield two or more smaller virion proteins. Cleavage is often one of the terminal events in the assembly of the virion and it can occur in situ aftel" most of the proteins are already in place.

Although most virion polypeptides have a structural role, some have enzymatic activity. Many viruses contain a few molecules of an internal protein that functions as a transcriptase, one of the two kinds of peplomers in the envelope of myxoviruses has neuraminidase activity, and a variety of other enzymes are found in the virions of the larger, more complex viruses.

In addition to polypeptides that occur as part of the virion, a large part of the viral genome codes for polypeptides that have a functional,role during viral multiplication but are not incorporated into viral particles. Few of these 'nonstructural viral proteins' have been characterized.

Except for the large and complex poxviruses, which constitute a special case, lipid and carbohydrate are found only in viral envelopes and are always of cellular origin. The lipids of viral envelopes are characteristic of the cell of origin, though minor differences between the viral envelope and the normal plasma membrane may be demonstrable. About 50--60 per cent of the lipid is phospholipid and most of the remainder (20-30 per cent) is cholesterol. Some of the viral carbohydrate occurs in the envelope as glycolipid characteristic of the cell of origin, but most of it is part of the glycoprotein peplomers that project from the viral envelope.

Three structural classes of viruses of vertebrates can be distinguished: isometric particles, which are usually 'naked' but in some families are enclosed within a lipoprotein envelope; long tubular nucleoprotein structures, always surrounded by a lipoprotein envelope; and in a few groups, a more complex structure. TERMINOLOGY Virion (plural, virions) is used as a synonym for 'virus particle'. The protein coat of an isometric particle, or the elongated protein tube of viruses with helical symmetry, is called the capsid (Fig. 1) The chemical units are sometimes held together by disulfide bonds to form the structural units, hence the practice of using reducing agents in polyacrylamide gel electrophoresis when analyzing viral proteins to determine their constituent polypeptides. The structural units are held together to form the capsid by noncovalent bonds, which may be polar (salt and hydrogen bonds) or nonpolar (van der Waals and hydrophobic bonds). The capsids of some viruses are readily disrupted in molar calcium or sodium chloride, suggesting electrovalent bonds between the structural units; others are unaffected by salt and can only be disrupted by detergents, suggesting that they are hydrophobically bonded. The capsomers of isometric viruses are arranged with icosahedral symmetry, because the icosahedron is that polyhedron with cubic symmetry which, if constructed of identical subunits, would least distort the subunits or the bonds between them.

An icosahedron (Fig. 2) has 20 equilateral triangular faces, 12 vertices, where the corners of five triangles meet, and 30 edges, where the sides of adjacent pairs of triangles meet. It shows two-fold symmetry about an axis through the center of each edge ( Fig. 2A) , three-fold symmetry when rotated around an axis through the center of each triangular face (Fig. 2B) , and five-fold symmetry about an axis through each vertex (Fig. 2C ). Each triangular face may be thought of as containing, and being defined by, three asymmetric units (i.e. units that have no regular symmetry axes themselves) so that a minimum of 60 asymmetric units are required to construct an icosahedron.

The pattern seen on the surface of the virion need not reflect the way in which the structural units are bonded together, and gives no clue as to whether the structural units are constituted by single chemical units or are homo-or heteropolymers of the chemical units. However, the number of structural units in each capsomer can be guessed at from the arrangement and size of the capsomers (Fig. 2) .

All animal viruses whose genome is DNA have isometric (or complex) capsids, as do those whose genome is double-stranded RNA (Reoviridae) and the viruses of two large families (Picornaviridae and Togaviridae) whose genome consists of a single molecule of single-stranded RNA.

VIRUSES WITH TUBULAR NUCLEOCAPSIDS Tubular nucleocapsids are found in many families of viruses of vertebrates, but only among those whose genome consists of single-stranded RNA. None of these occurs 'naked'; the flexuous helical tubes are always inside lipoprotein envelopes (Fig.  1B) . The diameters of the nucleocapsids of several viruses have been measured, but in only a few cases is the length or the pitch of the helix known.

Although occasionally used in a more general way to refer to the outer viral coats of some complex viruses like the poxviruses, the term 'envelope' is best restricted to the outer lipoprotein coat of viruses that mature by budding through cellular membranes. Enveloped viruses contain 20-30 per cent lipid, all of which is found in the envelope. The lipid is derived from the cellular membranes through which the virus matures by budding, but all the polypeptides of viral envelopes are virusspecified. The herpetoviruses are the only viruses of vertebrates that mature by budding through the nuclear membrane, and their envelopes contain several virusspecified glycoproteins. All other enveloped viruses bud through cytoplasmic membranes, and contain one or more different polypeptides. The Togaviridae have an isometric core to which a lipid layer is directly applied, and virus-specified glycoprotein peplomers project from this. All animal viruses with tubular nucleocapsids are enveloped, and in these the lipid layer from which glycoprotein peplomers project is probably applied to a protein shell (the membrane protein; see Fig. 1 ), which may be relatively rigid, as in rhabdoviruses, or readily distorted (as in the myxoviruses), so that in negatively stained electron micrographs the virions appear to be pleomorphic.

Viruses that have large genomes have a correspondingly complex structure. Apart from the undetermined nature of the 'cores' of many of the isometric viruses (e.g. Herpetoviridae and Adenoviridae), the virions of the largest animal viruses (Poxviridae) have highly complex structures. The RNA viruses that have the largest (single-stranded) genomes, the Retroviridae, also have a highly complex structure with an envelope enclosing an icosahedral capsid that, in turn, surrounds a tubular nucleocapsid.

In 1966 the Ninth International Congress for Microbiology established the International Committee for the Nomenclature of Viruses, which published its first report 5 years later (Wildy, 1971) . In 1974 the name, but not the responsibilities, of this committee was changed to the International Committee for the Taxonomy of Viruses, and the second report was published in 1976 (Fenner, 1976) . The classification and nomenclature used in this article follows the latter report, but is restricted to the families and genera of viruses that infect vertebrate animals.

Because virologists believe that there are probably no phylogenetic relationships between viruses of different families, they have hesitated to establish any taxa higher than the family, although for convenience it is customary to group viruses as 'DNA viruses' and 'RNA viruses'. At the other end of the nomenclatural spectrum, there is hopeless confusion in the ways in which the terms 'species', 'type', 'subtype', and 'strain' are used. For example, 'types' of influenza virus exhibit no serological cross-reactivity and their nucleic acids do not hybridize; they are not classified as distinct species or genera. On the other hand, many alphaviruses and flaviviruses with distinct names, which exhibit extensive serological cross-reactivity, should perhaps be regarded as types within the same species. Serological cross-reactivity and nucleic acidhybridization tests are probably most useful for making comparisons at this 'species' level.

In the descriptions of families and genera in this article the four terms of the cryptograms of Gibbs et al. (1966) , as modified in Fenner (1976) , are shown. The data refer to the infective viral particle (the virion). The first term of the cryptogram describes the type of the nucleic acid (R= RNA, D = DNA)/strandedness (1, 2 = single-, double-stranded). The second term describes the molecular weight of the nucleic acid (in millions)/the percentage of nucleic acid in the virion. Where the genome of infective particles consists of separate pieces occurring together in a single virion the symbol 'X' indicates this fact and the figure gives the total molecular weight of the genome. The third term describes the outline of the virion/outline of nucleocapsid [S = essentially spherical; E = elongated with parallel sides, ends not rounded; additional letter 'e'= enveloped; U = elongated with parallel sides, end(s) rounded; X = complex]. The fourth term, which has three components, describes the kinds of host infected (V=vertebrate; I=invertebrate)/mode(s) of transmission (C= congenital; I = ingestion; O = contact; R = inhalation; Ve = invertebrate vector)/the kinds of vector (D/= diptera; Ac = tick or mite; Si = flea). The third term is omitted if no vector is known. An asterisk indicates that a particular property is not known.

The cryptograms constitute a useful shorthand description of theproperties of viral families, as can be seen from Table 2. CLASSIFICATION BASED ON PHYSICOCHEMICAL CRITERIA The International Committee on Taxonomy of Viruses has agreed that classification should be based on physicochemical criteria, and Bot upon such properties as host range or symptomatology. Tables 3 and 9 summarize data on the morphology and chemistry of the viruses of vertebrates, and Fig. 3 illustrates their size and structure. The structure of the brick-shaped virion is complex, consisting of a biconcave DNAcontaining core surrounded by several membranes of viral origin. There is a poxvirus group antigen which is probably an internal component of the virion, and can be demonstrated by complement fixation or gel diffusion tests. Several enzymes, including a transcriptase, are found within mature virions. Multiplication occurs in the cytoplasm and the virions mature in cytoplasmic foci. Occasionally, the virion may be released within a loose membrane derived from the cytoplasmic membrane. This is not essential for infectivity, and must be distinguished from the envelope of viruses that mature by budding through cellular membranes. tSome of these families (Poxviridae, Iridoviridae, Reoviridae, Rhabdoviridae and Picornaviridae) include genera or members that multiply only in invertebrates; others (Reoviridae and Rhabdoviridae) contain genera that multiply only in plants. Where the third (host) term includes the letter 'I' (Iridoviridae, Reoviridae, Bunyaviridae, Rhabdoviridae and Togaviridae) at least some of the viruses that infect vertebrates also multiply in vertebrates (i.e. they are arboviruses). The family is divided into several genera (Table 4) , arm several poxviruses have still to be classified. The properties outlined for the family apply to all the genera, except that the virions of members of genera Parapoxvirus and Capripoxvirus (see Table 4 ), and swinepox virus, are narrower than those of other poxviruses, and virions of orf have a distinctive surface structure. Species within each genus show a high degree of serological cross-reactivity by neutralization as well as complement fixation tests. Genetic recombination occurs within, but not between, genera; nongenetic reactivation (complementation) occurs between most poxviruses of vertebrates.

Poxviruses cause diseases in man, domestic and wild mammals, and birds. These are sometimes associated with single or multiple benign tumors of the skin, hut are more usually generalized infections, often with a widespread vesiculo-pustular rash. Several poxviruses are transmitted in nature by anthropods acting as mechanical vectors. The herpesviruses (herpes = creeping) are readily recognized by their morphology. Their icosahedral capsid is assembled in the nucleus and acquires an envelope as the virus matures by budding through the nuclear membrane.

Electron microscopic examination by negative staining of many previously unclassified viruses showed that several of them had large icosahedral capsids with 162 capsomers enclosed within lipoprotein envelopes, similar to the type species, herpes simplex virus. When examined further, such were found to be DNA viruses that multiplied in the nucleus, and have now been included in the family Herpetoviridae. Table 5 shows some of the viruses now regarded as members of this family. There is a group-specific antigen(s) associated with the nucleocapsids and demonstrable by immunodiffusion, and several type-specific antigens associated with the nucleocapsid and envelope. Some type-specific antigens cross-react (e.g. herpes simplex viruses type 1 and type 2 and B virus). Different herpesviruses cause a wide variety of types of infectious diseases, some localized and some generalized, often with a vesicular rash. A feature of many herpesvirus infections is prolonged latency associated with one or more episodes of recurrent clinical disease. The adenoviruses (adeno =gland) are non-enveloped icosahedral DNA viruses which multiply in the nuclei of infected cells, where they may produce a crystalline array of particles. Many serological types have been isolated from human sources.

These have an antigen that is shared by all members of the genus Mastadenovirus, but differs from the corresponding antigen of Aviadenovirus. Allocation to the family is made primarily on the basis of the characteristic size and symmetry of the virion as seen in electron micrographs (icosahedron with 252 capsomers). Most adenoviruses are associated with respiratory infection and many such infections are characterized by prolonged latency. Some multiply in the intestinal tract and are recovered in feces. Many adenoviruses, from both mammalian and avian sources, produce malignant tumors when inoculated into new-born hamsters.

In the laboratory, stable hybrids have been produced between certain adenoviruses and the Polyomavirus, SV40.

Family: Papovaviridae [/9/2: 3-5/7-13: S/S: V/O, Ve/Ac, Si]

The family Papovaviridae (sigla: Pa = papilloma; po = polyoma; va = vacuolating agent, SV40) encompasses two genera, Polyomavirus (poly = many; oma= tumor) and Papillomavirus (papilla = nipple; oma = tumor), which differ substantially in size and nucleic acid content of the virion (Table 7) but share many other properties. An important property of many papovaviruses is their capacity to produce tumors. In nature, the papillomaviruses produce single benign tumors (which may undergo malignant change) and are highly host specific; several of the polyomaviruses may cause primary malignant tumors within a short period of their inoculation into new-born rodents. Parvoviruses (parvo = small) are unique among the DNA viruses of vertebrates in that their genome is a single molecule of .single-stranded DNA. Two genera are recognized: several viruses of rodents which are 'normal' infectious viruses (Parvovirus) , and the adeno-associated viruses, which are able to replicate only in cells concurrently infected with an adenovirus. In the adeno-associated viruses the single strands of DNA found in a population of virions are complementary and anneal after extraction to form a double strand. The family Reoviridae (sigla: respiratory enteric orphan) contains three genera that infect vertebrates, Reovirus, Orbivirus and Rotavirus, which show minor differences in morphology and the size of their genome, but all are non-enveloped isometric viruses whose genome consists of ten pieces of double-stranded RNA (Table 10) .

Viruses of the genus Reovirus are widespread among many kinds of vertebrates, usually producing non-symptomatic infections. The orbiviruses, several of which cause disease in man (Colorado tick fever) or domestic animals (bluetongue), are transmitted by arthropods. The rotaviruses cause diarrheal diseases of man and calves.

Family: Retroviridae [R/l: 7-10/2: Se/*: V/C, I,O, R]

The outstanding characteristic of the family Retroviridae is that all members contain an RNA-directed DNA polymerase ('reverse transcriptase'). The genome is single-stranded RNA, with a molecular weight of 7-10 million, associated with a helical nucleocapsid, which is enclosed within a capsid with cubic symmetry. This is, in turn, enclosed within a lipoprotein envelope about 100 nm in .diameter, containing peplomers which confer type specificity. They mature by budding from the plasma membrane.

Although all members of the family share important characteristics that are not found in any other viruses (e.g. reverse transcriptase, structure) their classification Fenner et al., 1974) Subfamily: Oncovirinae Type C oncovirus group: lenkosis-leukemia-sarcoma viruses Includes the well studied murine leukemia and avian leukosis viruses (C-type particles). Some strains produce sarcomas, some leukemia, others fail to transform cells or to induce neoplasia. Carried in the senome of normal cells as a DNA copy of viral senome. Rodent strains show serological crossreactivity, but also have species-and type-specific antigens. tCharacteristics: Virion contains a virus-specified RNA-directed DNA polymerase and other enzymes. Genome is a linear molecule of single-stranded RNA, molecular weight 7-10 million, probably associated with tubular nucleocapsid. Structure of virion is complex, the nucleocapsid being enclosed within a capsid of cubic symmetry, which is enclosed in an envelope that carries type.specific antigens. Virion also contains species-specific (e.g. feline or murine) and interspecies-specific (e.g. avian or rodent) antigens.

They have all the physicochemical properties of retroviruses. Although they do not cause neoplastic disease, they will transform cells that are non-permissive for viral growth. The viruses of subfamily Spumavirinae (foamy agents) include a number of viruses of monkeys, cats, and cattle, that have no known pathogenic potential but have been frequently isolated from tumors (as 'passenger viruses') or healthy animals. They have a different morphology from other retroviruses and produce an intranuclear antigen as well as cytoplasmic antigens in infected cells, but they contain a reverse transcriptase and, like other retroviruses, are much more resistant to UV irradiation than other RNA viruses. The family Coronaviridae (corona = crown) comprises a single genus, Coronavirus, which consists of several enveloped RNA viruses with a tubular nucleocapsid 9 nm in diameter. The genome consists of single-stranded RNA of molecular weight 9 million. tCharacteristics: genome consists of single-stranded RHA, molecular weight 9 x l0 s daltons; tubular nucleocapsid 9 nm in diameter; lipoprotein envelope 80-120 nm in diameter with large pedunculated pepiomers; multiply in cytoplasm and mature by budding into cytoplasmic vacuoles.

The envelope carries characteristic pedunculated projections. Human strains cause common colds; in other animals coronaviruses infect the respiratory or alimentary tract, or may cause systemic disease.

Family; Paramyxoviridae [R/l: 5--8/1:

The paramyxoviruses (para=alongside; myxo=mucus) are enveloped viruses whose RNA occurs as a single linear molecule with a molecular weight of about 7 million (Table 13 ). The tubular nucleocapsid has a diameter of 18 nm and is about 1.0/~m long. It is enclosed within a pleomorphic lipoprotein envelope 150 nm or more in diameter; long filamentous forms with the same diameter also occur. tCharacteristics: single linear molecule of single-stranded RNA, 7×losdaltons, within tubular nucleocapsid 18nm in diameter; pleomorphic fipoprotein envelope 100-300 nm in diameter; virion contains a transcriptase; multiply in cytoplasm; mature by budding from cytoplasmic or intracytoplasmic membranes. Members of Paramyxovirus contain virus-specific hemagglutinin and neuraminidase, of Morbillivirus, only a hemagglutinin, of Pneumovirus neither.

There are three genera: Paramyxovirus, whose envelopes contain virus-specific hemagglutinin and neuraminidase antigens; MorbiUivirus, comprising the related viruses that cause measles, distemper and rinderpest, and Pneumovirus, which includes human respiratory syncytial virus and pneumon ~ virus of mice. Virions of genus Morbillivirus contain a hemagglutinin but not a neuraminidase; those of Pneumovirus have neither.

Some paramyxoviruses cause localized infections of the respiratory tract and several produce severe generalized diseases; among the latter some are characteristically associated with skin rashes.

Family: Bunyaviridae [R/l: ~6-~7/*: Se/E: 1, V/C, Ve/Ac, Di] This family, in which only one genus, Bunyavirus, has been named so far, comprises of about 100 serologically-related arthropod-borne viruses that can be allocated to some 10 groups. Most are mosquito-transmitted, and some of these show transovarial transmission in mosquitoes; some are transmitted by ticks. *Characteristics: genome consists of single-stranded RNA, occurring as several pieces, molecular weight 6-7 million, tubular nucleocapsid 12-15 nm in diameter, within lipoprotein envelope 90-100 nm in diameter. All multiply in and are transmitted by arthropods.

Morphologically, those that have been studied have enveloped roughly spherical virions 90-100 nm in diameter with a tubular nucleocapsid. Several other arboviruses serologically unrelated to those of the Bunyavirus genus have a similar morphology (Table 14) . Their genome consists of single-stranded RNA probably occurring in several pieces, with a total molecular weight of 6-7 million.

Family: Orthomyxoviridae [R/l: 24/1: Se/E: V/R] In early classifications, some members of two very different families, now distinguished from each other as orthomyxoviridae (ortho = correct; myxo = mucus) and Paramyxoviridae, were grouped together as Myxovirus. The common properties were an RNA genome, a tubular nucleocapsid, and a pleomorphic lipoprotein envelope that carried the properties of hemagglutination and enzymatic elution. The term 'myxovirus' is now only used as a vernacular expression to encompass the viruses that have these properties (viz. influenza, mumps, Newcastle disease, and parainfluenza viruses); it has no taxonomic status.

The family orthomyxoviridae comprises two genera; one, called Inltuenzavirus, includes two species, A and B, with their many subtypes and strains. The other genus, represented by influenza type C, has not yet been named. All members of the family have a fragmented genome consisting of eight pieces of single-stranded RNA, which accounts for the frequent genetic reassortment found in mixed infections. The virion contains two virus,specific enzymes; a surface neuraminidase and an internal transcriptase. tCharacteristics: genome consists of eight separate pieces of single-stranded RNA, total molecular weight 4 million; tubular nucleocapsid 6-9 nm diameter is type-specific antigen; lipoprotein envelope 80-120nm in diameter contains strain-specific hemagglutinin and neuraminidase antigens; virion contains a transcriptase; multiply in nucleus and cytoplasm; mature by budding from the plasma membrane. ~Includes fowl plague virus.

Influenzavirus A has been recovered from a number of different species of animals (birds, horses, and swine) as well as man; Influenzavirus B and influenza type C are specifically human pathogens. They are an important cause of respiratory disease in man and other animals, and some of the avian influenza viruses may cause severe generalized infections in birds. The family arenaviridae (arena = sand), which contains one genus, Arenavirus, was first defined by the electron microscopic appearance of the virions in thin sections, and serological cross-reactivity. The pleomorphic enveloped virions are 85-120 nm in diameter (sometimes larger), and have closely spaced peplomers. The structure of the nucleocapsid is unknown, but in thin sections the interior of the particle is seen to contain a variable number of electron-dense granules 20-30 nm in diameter, hence the name.

All members of the genus are associated with chronic inapparent infections of rodents; some cause acute generalized diseases in. other hosts (e.g. Lassa fever virus in man). . tCharacteristics: single-stranded RNA probably in several pieces, total molecular weight 3.2-5.6 million; lipoprotein envelope 85-300nm in diameter; multiply in cytoplasm; mature by budding from plasma membrane. All members share a group-specific antigen. Envelope encloses granules 20-30 nm in diameter; some of these are cellular ribosomes. There is a virion-associated transcriptase.

Family: Rhabdoviridae JR/l: 3.5-4.6/2-3: Ue/E: I, V, C, O, Ve]

The rhabdoviruses (rhabdo = rod) are enveloped RNA viruses with single-stranded RNA with a molecular weight of about 4 million. The RNA is associated with a very regular double-helical nucleocapsid 5 nm in diameter, enclosed within a bullet-shaped shell that measures about 175 x 75 nm (Table 17) .

The family contains two named genera, Vesiculovirus and Lyssavirus, that infect vertebrates and some viruses ~ot yet allocated to a genus; some insect and plant viruses may also belong to this family.

Family: Togaviridae JR/l: 3.5-4/5-8: Se/S: I, V/C, I, O, R, Ve/Ac, Di] During the last quarter century intensive world-wide efforts have been made to recover viruses which would multiply in both arthropods and vertebrates, and some 200 different agents with these biological properties are now known. They have been called 'arthropod-borne viruses', a name which was shortened to 'arborviruses' and then (in order to avoid the connotation of 'tree') to 'arboviruses'. The arboviruses have been defined, on epidemiological grounds (mode of transmission), as a group comparable to the 'respiratory viruses'. Arboviruses are viruses which, in nature, can infect arthropods that ingest infected vertebrate blood, can multiply in the arthropod tissues, and can then be transmitted by bite to susceptible vertebrates.

For many years arboviruses have been recovered from vertebrate tissues and suspensions of arthropods by the intracerebral inoculation of mice, and advantage has been taken of certain chemical and physical properties found to be commonly associated with them to avoid confusion with murine picornaviruses. The property generally tested was sensitivity to lipid solvents. Many arboviruses have lipoprotein envelopes and their infectivity is destroyed by these reagents. There was thus a tendency to equate sensitivity to lipid solvents with 'arbovirus'. During the last decade it has been recognized that the arbovirus group is quite heterogeneous in its physicochemical properties. Some members are not enveloped (Orbivirus, Nodamura virus), and those sensitive to lipid solvents belong to at least three families (Togaviridae, Rhabdoviridae, and Bunyaviridae).

This preamble has been necessary because in the past the term 'arboviruses' has been regarded as applying particularly to viruses with the physicochemical properties of the group A and group B arboviruses. These viruses now form two genera (Alphavirus and Flavivirus) of the family Togaviridae (toga = cloak). The family also contains two other genera, Rubivirus and Pestivirus for which no arthropod vectors are known (Table 18) .

Genus: Alphavirus [R/l: 4/5-6: SelS: I, V, VelDi]. The alphaviruses (alpha = Greek letter A), formerly known as the group A arboviruses, have the familial characteristics (Table 18 ) and show serological cross-reactivity by the hemagglutinin-inhibition test. The arthropod vectors are mosquitoes, but some alphaviruses may be transmitted congenitally by vertebrates. In nature, they usually cause inapparent infections of birdS, reptiles, or mammals, but some can cause generalized infections associated with encephalitis in man and in other mammals.

Genus: Flavivirus [R/l: 4/8: SelS: I, V, C, O, VelAc, D/]. This genus (flaviyellow) comprises the group B arboviruses. All members show serological crossreactivity. The arthropod vectors may be ticks or mosquitoes, and some of them may be transmitted by the ingestion of contaminated milk. They differ from the alphaviruses in that budding usually occurs into cytoplasmic vacuoles rather than from the plasma membrane. Most cause inapparent infections in mammals and less commonly in birds, but generalized infections of man may occur with visceral symptomatology (e.g. yellow fever), rashes (e.g. dengue), or encephalitis (e.g. Japanese encephalitis).

Genus: Rubivirus [R/I: 3.5/*: Se/S: V/C, R] contains oniy one species, rubella virus, causing a minor generalized exanthematous disease in man, which may be associated with congenital defects in the new-born when pregnant women are infected during the first three months of pregnancy.

Genus: Pestivirus JR/l: 4/*: Se/S: V/C, I, R]. These are viruses recovered from cattle and swine, whose virions are physicochemically like togaviruses; but they are not transmitted by arthropods. Hog cholera virus may be transmitted congenitally. (pH3) and have a buoyant density (in CsC1) of 1.34-1.35 g/cm 3. They are primarily inhabitants of the intestines, and a large number of serotypes have been found in the feces of man and of various animals.

The enteroviruses of man have been sulddivided into three major subgroups: poliovirus, three serotypes; echovirus (acronym: echo=enteric cytopathogenic human orphan), 34 serotypes; and coxsackievirus (Coxsackie = town in New York State), 24 serotypes of type A and six of type B. The polioviruses, which show some serological cross-reactivity, are distinguished by their capacity to paralyze humans. Coxsackieviruses were originally defined in terms of their capacity to multiply in infant mice, but subsequently some echoviruses were found to do the same. It has been recommended that all future enteroviruses that are discovered should be numbered sequentially from 68, irrespective to subgroups. Some workers distinguish a separate genus Cardiovirus (see Table 19 ) on the basis of the resemblance of several species which differ in other respects from Enterovirus.

Genus: Rhinovirus [R/l: 2.3-2.8/30: S/S: V/R]. The rhinoviruses resemble the enteroviruses in several characteristics but they are acid labile (pH 3) and have a buoyant density (in CsCI) of 1.38-1.43 g/cm 3. Most have a low ceiling temperature of growth and are characteristically found in the upper respiratory tract of man and various animals.

There are a large number of different serotypes of human rhinoviruses. Foot-and-mouth disease virus, of which there are several serotypes, resembles rhinoviruses in some respects, but not in others (Table 19) , and is sometimes classified as a separate genus

Most rhinoviruses cause mild localized infections of the upper respiratory tract, but foot-and-mouth disease virus causes a severe generalized disease with rash in cattle.

Genus: Calicivirus [R/l: 2.8120-30: S/S: V/I, R]. This genus differs substantially from the other genera of the Picornaviridae, both in its morphology and the chemical composition of the capsid, the outstanding difference being the distinctive 'chunky' arrangement of the capsomers. The other properties of the genus are those common to the Picornaviridae, with acid stability and a buoyant density intermediate between those of Enterovirus and Rhinovirus.

There remain a few important viruses, from the point of view of human disease, that have not yet been characterized sufficiently as physicochemical entities for classification.

Experiments with human volunteers have shown that the diseases commonly known as infective hepatitis and serum hepatitis are caused by two viruses that differ serologically, in their clinical expression, and in their usual routes of transmission. Because both can be transmitted orally it is better to use noncommital names for them; 'serum hepatitis' is now termed hepatitis B; infective hepatitis, hepatitis A. Study of these viruses has been greatly inhibited by the lack of susceptible laboratory animals (chimpanzees may get clinical hepatitis; marmosets and rhesus monkeys subclinical infection, while other laboratory animals are insusceptible), and the difficulty of obtaining reproducible cytopathic changes in cultured cells. The recognition in the sera of cases of serum hepatitis of lipoprotein particles of characteristic serological specificity, 'Australia antigen', now hepatitis B antigen (HB-Ag), has led to a great expansion in studies on the incidence and pathogenesis of hepatitis B, but the actual virions have not yet been analysed.

Virus particles found in the feces of patients suffering from hepatitis A have been identified as the causative agents by immunoelectron microscopy; they are small isometric virions and it has been suggested that they may belong to the family Parvoviridae.

Four diseases of similar nature, scrapie of sheep, transmissible encephalopathy of mink, and kuru and Creutzfeld-Jakob disease in man appear to be caused by similar agents, which differ from all known viruses by being non-immunogenic. The causative agents are filtrable, highly heat-resistant, and highly resistant to ionizing radiation. It has been suggested that they may be small molecules of naked RNA, protected by their close association with cellular membranes and thus similar to the 'viroids' of some plant diseases, like potato spindle tuber disease. A definitive description of these agents is still awaited.

In Germany, in 1967, a small outbreak of a serious new disease occurred in laboratory workers who had handled the tissues of recently imported vervet monkeys. Since then the virus has been recovered from sporadic cases of hemorrhagic fever among human patients in Africa. The causative agent grows in cultured cells and kills guinea pigs. Studies with inhibitors suggest that it contains RNA; of known viruses it most closely resembles rhabdoviruses in structure but is much larger and more pleomorphic.

All show serological cross-. reactivity and all are mosquito-borne viruses. Members: Equine encephalitis viruses--Western, Eastern, and Venezuelan

All show serological cross-reactivity, some are mosquito-borne and some are tick-borne viruses. Members: yellow fever

Hog cholera virus *Type genus: Alphavirus. tCharacteristics: single linear molecule of single-stranded RIgA of molecular weight 4 x 106 daltons, within a capsid of cubic symmetry, 20--40 nm in diameter, which is enclosed within a llpoprotein envelope 40-70 nm in diameter; multiply in cytoplasm and mature by budding from cytoplasmic (Alphavirus) or intracytoplasmic (Flavivirus) membranes; purified viral RNA is infectious. REFERENCES It would require literally thousands of references to justify the statements made in this review. The interested reader is therefore referred to two source books

The Classification and Nomenclature of Viruses. Second Report of the International Committee on Taxonomy of Viruses

The Biology of Animal Viruses

What's in a virus name?

Classification and nomenclature of viruses. First Report of the International Committee on Nomenclature of Viruses