key: cord-0035815-6h7r65zv
authors: Gillet, Laurent; Vanderplasschen, Alain
title: Viral Subversion of the Immune System
date: 2005
journal: Applications of Gene-Based Technologies for Improving Animal Production and Health in Developing Countries
DOI: 10.1007/1-4020-3312-5_20
sha: 1544c11905c055a675bf42b8f569b7712604c9c0
doc_id: 35815
cord_uid: 6h7r65zv

The continuous interactions between host and viruses during their co-evolution have shaped not only the immune system but also the countermeasures used by viruses. Studies in the last decade have described the diverse arrays of pathways and molecular targets that are used by viruses to elude immune detection or destruction, or both. These include targeting of pathways for major histocompatibility complex class I and class II antigen presentation, natural killer cell recognition, apoptosis, cytokine signalling, and complement activation. This paper provides an overview of the viral immune-evasion mechanisms described to date. It highlights the contribution of this field to our understanding of the immune system, and the importance of understanding this aspect of the biology of viral infection to develop efficacious and safe vaccines.

The continuous interactions between hosts and viruses during their coevolution have shaped not only the immune system but also the countermeasures used by viruses. The evasion strategies that viruses have devised are highly diverse, ranging from the passive to the active. Passive evasion strategies comprise hiding inside the infected host cell in a dormant form or creating a broad antigenetic diversity among the progeny virions during each replication cycle (as exploited, for example, by retroviruses), thus evading or staying one step ahead of the immune response. Active mechanisms include interferences with pathways for major histocompatibility complex (MHC) class I and class II antigen presentation, natural killer (NK) cell recognition, cytokine signalling, apoptosis of infected cells, and complement activation. In this review, the authors provide an overview of the different active mechanisms that viruses use to evade host immune responses. Due to space constraints, those mechanisms will be presented concisely in pairs of associated figures and tables. The basic concepts of the components of the immune system targeted by the viruses are described in the figures, while viral strategies are listed in the corresponding tables. To save space, viruses are cited using the abbreviations of the International Committee for Taxonomy of Viruses.

CD8-positive cells play an important role in immunity against viruses. Just how important these cells are is demonstrated by the evolution of viral strategies for blocking the genesis or the display of viral peptide-MHC class I complexes on the surface of viral infected cells. To enhance the understanding of this field, the manner in which viral proteins are processed for recognition by virus-specific CD8+ T cells is briefly described (Figure 1 ). In the infected cells, peptides are generated from by-products of proteasomal degradation. Most of the substrates consist of defective ribosomal products (DRiPs). Peptides are then transported into the endoplasmic reticulum (ER) by the TAP protein. Here, MHC class I molecules are folded through the actions of general purpose molecular chaperones working with a dedicated chaperone (Tapasin) that tethers MHC class 1 to TAP. After peptide binding, MHC class I molecules dissociate from TAP, leave the ER and migrate to the plasma membrane through the Golgi complex. As viral peptide-MHC class I complexes accumulate on the cell surface, they have a greater chance of triggering activation by CD8+ T cells with a cognate receptor. Viruses have been shown to interfere with virtually every step of T cell antigen processing and presentation ( Figure 1 and Table 1 ). The viral proteins involved in such mechanisms have been called VIPRs (pronounced "viper") for viral proteins interfering with antigen presentation. They are listed in Table 1 together with their mechanism of action. For an excellent review on this subject, see that of Yewdell and Hill (2002) . The classical MHC class I pathway is depicted with reference to viral interfering proteins listed in Table 1 . Peptides are derived from DRiPs through the action of proteasomes and transported into the ER by the TAP protein. Nascent MHC class I molecules bind to TAP via tapasin. Binding of peptide to MHC class I molecules releases them from the ER. Peptide-MHC class I molecules then migrate to the cell surface. VIPRs have been shown to interfere with virtually every step of T cell antigen processing and presentation, namely (1) prevention of peptide degradation; (2) inhibition of peptide translocation in the ER, the inhibitory viral protein being either on the cytosolic side (2a) or in the lumen of the ER (2b); (3) retention of MHC class I molecules in the ER (3a) or in the transGolgi network (TGN) (3c), or by targeting of ER MHC class I molecules for degradation by the proteoasomes (3b); (4) reduction of peptide-MHC class I complexes exposed on the cell surface by inhibition of their migration to the cell surface, by increasing their endocytosis from the cell surface and by increasing their degradation into lysosomes; and (5) inhibition of T CD8+ cell recognition of cell surface peptide-MHC class I complexes. The VIPRs acting at those steps are listed in Table 1 . Yin, Maoury and Fahraeus, 2003 . [3] Gilbert et al., 1993 . [4] Galocha et al., 1997 . [6] Hinkley, Hill and Srikumaran, 1998 . [7] Hengel et al., 1996 Ahn et al., 1997 . [9] Lehner et al., 1997 . [10] Cox, Bennink and Yewdell, 1991 . [11] Burgert and Kvist, 1987 Jefferies and Burgert, 1990 . [13] Bennett et al., 1999 . [15] Jones, et al., 1996 . [16] Kavanagh, Koszinowski and Hill, 2001 . [17] Wiertz et al., 1996 . [18] Boname and Stevenson, 2001 . [19] Lybarger et al., 2003 . [20] Kerkau et al., 1997 . [21] Johnson et al., 2001 . [22] Ziegler et al., 1997 Reusch et al., 1999 . [24] Le Gall et al., 1998 . [25] Cohen et al., 1999 [26] Rappocciolo, Birch and Ellis, 2003 . [27] Hewitt et al., 2002 . [28] Kleijnen et al., 1997 . Viral mechanisms interfering with NK cell functions fall into five categories, namely (1) expression of virally encoded MHC class I homologues that serve as NK cell decoys and ligate inhibitory receptors to block NK cytotoxicity; (2) selective modulation of MHC class I allele expression. Some viruses are able to down-regulate MHC class I molecules that are efficient for presentation of viral peptides to CD8+ cytotoxic T cells (such as HLA-A and HLA-B) without affecting or even increasing the expression of HLA-C and HLA-E, the dominant ligands for NK cell inhibitory receptors; (3) through the various mechanisms listed in Table 2 , some viruses are capable of inhibiting the function of NK activatory receptor; (4) other viruses interfere with the cytokine pathways relevant to NK cell activation by producing virally encoded cytokine-binding proteins or cytokine antagonist; and (5) viruses can also directly inhibit NK cells by infecting them or by using viral envelope proteins to ligate NK cell inhibitory receptor.

NK cells are lymphocytes that, in contrast to B and T cells, do not undergo genetic recombination events to increase their affinity for particular ligands, and are therefore considered as part of the innate immune system. They are capable of mediating cytotoxic activity and producing cytokines after ligation of a variety of germline-encoded receptors. Like CD8+ T cells, NK cells mediate direct lysis of target cells by releasing cytotoxic granules containing perforin and granzymes, or by binding to apoptosis-inducing receptors on the target cells. Several receptors that can activate NK cells have been identified, among which some recognize viral proteins (Orange et al., 2002) . Due to the possible consequences of NK cell activation, normal host cells must inhibit NK activity. Various inhibitory receptors are consistently expressed by a subset of NK cells. These receptors bind to host MHC class I molecules and transmit inhibitory signals to the NK cells.

As noted above, many viruses have acquired effective means of avoiding T cell antigen presentation, thus avoiding T cell adaptive immune response. However, by eluding T cells, the viruses might have increased their susceptibility to NK cell-mediated defences. Consequently, in addition to the inhibition of T cell antigen presentation, some viruses have also acquired mechanisms to evade the action of NK cells. These mechanisms fall into five categories, presented in Figure 2 ; the viruses known to have acquired such mechanisms are listed Table 2 . For an excellent review of the viral evasion of NK cells, see Orange et al. (2002) . MHC class II and chains and the invariant chain (Li) are expressed constitutively or in response to IFN-g stimulation. These molecules assemble in the ER to form the --Li complexes that are then transported from the ER through the Golgi apparatus to the TGN, where the complexes are sorted to endosomes in response to signals present in the cytoplasmic tail of Li. In early endosomes, Li is progressively degraded by low-pH proteases so that fragments of it remain bound to the peptide-binding groove formed by the -chains. The MHC class II complexes then traffic into more acidic late endosomes and prelysosomal compartments known as MHC class II loading compartment (MIIC). Viral antigens can reach the endocytic pathway by phagocytosis, endocytosis or recycling of internal vesicules (site of virus assembly). Antigens delivered into the endocytic pathway are degraded by aciddependent proteases to form peptides that are delivered to MIIC and loaded onto MHC class II -dimers. Exchange of peptide antigens for Li fragments occurs in collaboration with class II-like -dimers called DM. From the MIIC, peptide-loaded class II moves to the cell surface for presentation to CD4+ T cells. Viral mechanisms interfering with MHC class II antigen presentation fall into 5 categories: (1) inhibition of the IFN-transduction cascade leading to the expression of MHC class II; (2) Inhibition of the association of the and chains with the Li chains; (3) redirecting the and b chains and DM for degradation by the proteasome; (4) preventing MHC class II from reaching the endocytic compartment; and (5) interfering with MHC class II processing and acidification of the endosome.

CD4-positive cells can recognize viral antigens expressed on virusinfected cells expressing MHC class II molecules to act cytolytically, to produce antiviral cytokines or to coordinate the antiviral immune response. MHC class II molecules are expressed constitutively by thymic epithelial cells, activated T cells and professional antigen-presenting cells, while in other cells, such as fibroblasts, keratinocytes, endothelial, epithelial and glial cells, their expression require IFN-γ stimulation. The latter induces the expression of MHC-II molecules through a complex cascade of factors (reviewed in Hegde, Chevalier and Johnson, 2003) .

From the recent literature, it appears that viral inhibition of MHC class II antigen presentation is designed to prevent presentation of endogenous viral antigens in virus-infected cells rather than presentation of exogenous antigens in professional antigen-presenting cells. Andresson et al., 1995. [13] Tong et al., 1998. To enhance the understanding of this field, Figure 3 illustrates how viral peptides are processed for presentation in association with MHC class II molecules on the surface of an infected host cell. Some of the viral mechanisms acquired by viruses to interfere with this process are listed in Table 3 . For an excellent review of this topic, see Hegde, Chevalier and Johnson (2003) . The strategies acquired by viruses to interfere with or to exploit host cytokines, chemokines and their receptors can be classified into 5 categories: (1) some viruses encode membrane anchored molecules able to bind host chemokine and eventually transduce a signal. Because these viral molecules have sequence similarity with host cellular receptors, they have been called chemokine receptors; (2) other viruses encode soluble proteins capable of binding to chemokines and preventing their action on target cells. Because these viral proteins are not homologues of host cellular proteins, they have been called chemokine binding protein rather than chemokine receptor; similarly, (3) viral encoded membrane anchored cytokine receptors; and (4) soluble cytokine receptors or soluble cytokine binding proteins have been described; (5) viruses are known to encode homologues of cytokines or chemokines.

Viral infection induces the production of cytokines and chemokines playing crucial roles in inducing the migration and activation of immune cells to areas of infection; in immune regulation; in anti-viral defence; as well as in the capacity of target cells to support virus replication. For example, cytokines such as interferons (IFN) and tumour necrosis factor (TNF) induce intracellular pathways that activate an anti-viral state or apoptosis, and thereby contribute to limit viral replication. A very large number of cytokines induce mechanisms that enhance immune recognition, or immune responses that protect against viral infection. Finally, some antiviral cytokines mediate killing of infected cells by NK cells or cytotoxic T lymphocytes. Therefore, it is not surprising to find that cytokines, chemokines and their receptors are targets of viral immune-evasion strategies. The different strategies developed by viruses to interfere with or to exploit host cytokines, chemokines or their receptors are illustrated in Figure 4 . Example of viruses known to have acquired such strategies are listed in the accompanying Table 4 . For an excellent review of this topic, see the recent review by Alcami (2003) . 

Replication of viruses may stimulate suicide of the host cell directly or via recognition by immune effector cells. These cells (cytolytic T cells and NK cells) induce cell death by secretion of cytotoxic cytokines such as TNFs and by processes requiring direct cell-cell contact, such as release of perforin and granzyme. This form of programmed cell death is called apoptosis. Apoptosis is an orchestrated biochemical process that leads ultimately to the demise of the cell, initiated by both internal sensors (intrinsic pathway, mitochondria dependent) and external stimuli (extrinsic pathway, death receptor mediated). Apoptosis can be initiated by two main pathways. The extrinsic pathway is triggered by death ligands binding to their cognate death receptors. These receptors then multimerize and their death domains (DDs) interact with the DDs of adaptator proteins that bind to pro-caspase 8 and/or pro-caspase 10 to form the DISC. This ends with pro-caspase cleavage in their active form. These caspases can then cleave Bid and activate the effector caspase cascade. On the other end, internal sensors initiate the intrinsic pathway via a process that results in heterooligomeric pores formation in the outer membrane of the mitochondria. Factors such as cytochrom c, Smac and Omi are then released in the cytoplasm where cytochrom c promotes formation of the apoptosome, resulting in autocatalytic activation of caspase 9, which initiates the effector caspase cascade. Caspases activation is negatively regulated by IAP, which are counter-balanced by proapoptotic Smac and Omi. Viral mechanisms of apoptosis inhibition fall into 4 main categories: (1) modulating of death receptors signalling; (2) regulation of caspase; (3) mimicking Bcl-2; and (4) blinding the internal sensors.

In the case of replicating viruses, apoptosis can be viewed as an altruistic defence mechanism by which the host infected cell commits suicide in order to prevent virus spread in the infected host. Indeed, premature cell death would enable viruses to maximally replicate or to establish latency. Apoptosis is a complex and highly regulated process. Many viruses have acquired mechanisms to inhibit this important biological process, by targeting different steps. These mechanisms of viral inhibition of apoptosis can be classified into four main classes: modulation of death receptor signalling; caspase regulation; Bcl-2 mimicking; and internal sensors blinding. They are described in Figure 5 . Viral proteins inhibiting apoptosis are listed in Table 5 , together with their mechanism of action. For an excellent review of this subject, see Benedict, Norris and Ware (2002). NOTES: (1) Site of action. Numbers refer to paths identified in Figure 5 . (2) 

Complement is part of the innate immune system and is activated in a cascade manner through two main pathways, known as the classical and the alternative, and illustrated in Figure 6 . Complement is part of the innate immune system and is activated in a cascade manner through two main pathways, known as the classical and the alternative pathways. The classical pathway is activated by the recognition proteins C1q or mannose-binding lectin, which bind respectively to charge clusters or neutral sugars on targets. In contrast, activation of the alternative pathway is a default process that proceeds unless down-regulated by specific mechanisms. Complement activation results in cleavage and activation of C3 and deposition of opsonic C3 fragments on surfaces. Subsequent cleavage of C5 leads to assembly of the membrane attack complex (C5b,6,7,8,9) , which disrupts lipid bilayers. Viruses have developed different strategies acting at different stages of the complement cascade in order to evade complement-mediated destruction. These are listed in Table 6 , and are referred to in this figure. These strategies fall into three main categories: (1) some viruses interfere with the classical pathway by avoiding complement binding to antibody-antigen complexes, either by shedding or internalization of these complexes from the cell surface or by expressing virallyencoded Fc receptor on the cell surface; (2) other viruses encode and express functional homologue of cellular regulators of complement activation (RCA), protecting their lipid envelope and the membrane of the infected cell; and (3) some viruses can incorporate host complement RCA in their envelope and/or up-regulate expression of these proteins in infected cells.

Complement activation on host cells is prevented by several membrane regulators of complement activation (RCA), the activity of which is predominantly restricted to complement of the same species, a phenomenon called homologous restriction. These proteins down-regulate complement activity at two steps in the classical and the alternative pathways: complement receptor 1 (CD35) and decay-accelerating factor (CD55) inhibit the formation and accelerate the decay of the classical pathway and alternative pathway C3-activating enzymes (C3 convertases); complement receptor 1 and membrane cofactor protein (CD46) act as cofactors for Factor I (a serum protease), which catabolizes C4b and C3b, thereby inhibiting formation of the C3 convertases C4b2a and C3bBb; finally, at the end of the complement cascade, CD59 and possibly also homologous restriction factor (C8-binding protein) prevent the formation of the membrane attack complex.

In general, micro-organisms lack mammalian RCA and thus cannot restrict complement deposition and amplification on their surfaces. However, the toxicity of the complement system has selected viruses that have acquired countermeasures. The viral strategies to evade complementmediated destruction are summarized in Table 6 . For a recent review of this topic, see that of Favoreel et al. (2003) . Thale et al., 1994 . [8] Oleszak et al., 1993 . [9] Howard et al., 1998 . [10] Kotwal et al., 1990 [11] Rosengard et al., 2002 . [12] Fodor et al., 1995 [13] Mold et al., 1988 . [14] Friedman et al., 1984 . [15] Huemer et al., 1993 . [16] Kostavasili et al., 1997 . [17] Rother et al., 1994 [18] Spiller et al., 1996. [19] Maeda et al., 2002. [20] Vanderplasschen et al., 1998. [21] Saifuddin et al., 1995 . [22] Spear et al., 1995 Hirsch, Griffin and Winkelstein, 1981. 

During the millions of years they have been co-evolving with their host, viruses have learned how to manipulate host immune control mechanisms. The review of the immune evasion strategies acquired by viruses revealed several fascinating aspects of this field. First, it is remarkable that individual virus families have targeted many common immunological principles. Second, the analysis of viral immunoregulatory proteins revealed that they belong to two classes: those encoded by genes with and those encoded by genes without sequence homology to cellular genes. While the former indicates that viruses have "stolen" genes from the host that were subsequently modified for the benefit of the virus, the latter suggests acquisitions through a mechanism of convergent evolution.

Viruses are obligate parasites that live "on the edge". On the one hand, they need to impair the immune response of their host to be able to replicate and to avoid eradication; but, on the other hand, they need to respect the host immune response in order to ensure their host's (and hence their own) survival. In other words, the perfect adaptation of a virus to its host would represent a virus able to complete its biological cycle without inducing clinical symptoms. Further studies are required to determine the roles of viral immune-evasion mechanisms in this delicate equilibrium. Indeed, most of the studies cited in this review have investigated the ability of viral genes to interfere with the host immune response in vitro. However, only in vivo experiments will be able to determine the real biological functions of these viral immune-evasion mechanisms. A beautiful example supporting this statement has been provided by the study of vaccinia virus IL-1β receptor. Indeed, while this viral product was thought to contribute to the pathogenicity of the virus, it is interesting to observe that deletion of the corresponding gene enhanced virus virulence and the onset of fever, suggesting that the purpose of a least some of the immune-evasion mechanisms is to reduce immunopathology caused by viral infection (Alcami and Smith, 1996) .

In conclusion, this review highlights the complexity and the importance of viral immune-evasion strategies in the host-virus relationship. 

The EER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP

Molecular mechanism and species specificity of TAP inhibition by herpes simplex virus protein ICP47

Human cytomegalovirus inhibits antigen presentation by a sequential multistep process

HIV-1 Tat protein mimicry of chemokines

Viral mimicry of cytokines, chemokines and their receptors

A soluble receptor for interleukin-1-beta encoded by vaccinia virus -a novel mechanism of virus modulation of the host response to infection

Vaccinia, cowpox, and camelpox viruses encode soluble gamma-interferon receptors with novel broad species specificity

A mechanism for the inhibition of fever by a virus

Blockade of chemokine activity by a soluble chemokine binding protein from vaccinia virus

An African swine fever virus Bcl-2 homolog, 5-HL, suppresses apoptotic cell death

Vacuolar H+ATPase mutants transform cells and define a binding site for the papillomavirus E5 on oncoprotein

Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6

Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors

Human herpesvirus KSHV, encodes a constitutively active G-protein-coupled receptor linked to cell proliferation

Identification and expression of human cytomegalovirus transcription units coding for two distinct Fc gamma receptor homologs

Human cytomegalo-virus encodes a glycoprotein homologous to MHC class-I antigens

Virus subversion of the MHC class I peptide-loading complex

Expression of the myxoma virus tumor necrosis factor receptor homologue and M11L genes required to prevent virus-induced apoptosis in infected rabbit lymphocytes

The HCMV gene products US11 and US2 differ in their ability to attack allelic forms of murine major histocompatibility complex (MHC) class I heavy chains

Pseudorabies virus (PRV) is protected from complement attack by cellular factors and glycoprotein C (gC)

Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells

Epstein-Barr virus encodes a novel homolog of the bcl-2 oncogene that inhibits apoptosis and associates with Bax and Bak

A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases

Human cytomegalovirus inhibits major histocompatability complex class II expression by disruption of the Jak/Stat pathway

Human cytomegalovirus inhibits IFN-alpha-stimulated antiviral and immunoregulatory responses by blocking multiple levels of IFN-alpha signal transduction

RANTES binding and down-regulation by a novel human herpesvirus-6 beta chemokin receptor

Epstein-Barr virus regulates activation and processing of the 3RD component of complement

Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI

Myxoma virus M-T7. a secreted homolog of the interferon-gamma receptor, is a critical virulence factor for the development of myxomatosis in European rabbits

Viral exploitation and subversion of the immune system through chemokine mimicry

Herpesvirus Saimiri encodes a functional homolog of the human bcl-2 oncogene

Herpes simplex virus type 1 targets the MHC class II processing pathway for immune evasion

The vaccinia virus A41L protein is a soluble 30 kDa glycoprotein that affects virus virulence

African swine fever virus IAP homolog inhibits caspase activation and promotes cell survival in mammalian cells

Appearance of immunoglobulin-GFC receptor in cultured human cells infected with varicella-zoster virus

Molecular mimicry between S peplomer proteins of coronaviruses (MHV, BCV, TGEV and IBV) and Fc receptor

Viral evasion of natural killer cells

Temporally distinct patterns of P53-dependent and P53-independent apoptosis during mouse lens development

Cowpox virus encodes a fifth member of the tumor necrosis factor receptor family: A soluble, secreted CD30 homologue

Marek's disease virus (MDV) encodes an interleukin-8 homolog (vIL-8): characterization of the vIL-8 protein and a vIL-8 deletion mutant MDV

The MHC class I homolog of human cytomegalovirus is resistant to down-regulation mediated by the unique short region protein (US)2, US3, US6, and US11 gene products

A broad spectrum secreted chemokine binding protein encoded by a herpesvirus

Cytomegalovirus encodes a potent alpha chemokine

NK cell inactivation by dendritic cells is dependent on LFA-1-mediated induction of calcium-calmodulin kinase II: Inhibition by HIV-1 Tat C-terminal domain

Regulation of class II expression in monocytic cells after HIV-1 infection

Down-regulation of MHC class I expression by equine herpesvirus-1

Vaccinia virus CrmE encodes a soluble and cell surface tumor necrosis factor receptor that contributes to virus virulence

A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation

The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells

The genome of equine herpesvirus type-2 harbors an interleukin-10 (IL10)-like gene

Variola virus immune evasion design: Expression of a highly efficient inhibitor of human complement

Inhibition of complement-mediated cytolysis by the terminal complement inhibitor of herpesvirus Saimiri

Murine cytomegalovirus CC chemokine homolog MCK-2 (m131-129) is a determinant of dissemination that increases inflammation at initial sites of infection

Cytomegalovirus-encoded beta chemokine promotes monocyte-associated viremia in the host

Role of virion-associated glycosylphosphatidylinositol-linked proteins CD55 and CD59 in complement resistance of cell line-derived and primary isolates of HIV-L

CrmE, a novel soluble tumor necrosis factor receptor encoded by poxviruses

Inhibition of type 1 cytokinemediated inflammation by a soluble CD30 homologue encoded by ectromelia (mousepox) virus

Kaposi's sarcomaassociated herpesvirus encodes a functional Bcl-2 homologue

Down-modulation of mature major histocompatibility complex class II and up-regulation of invariant chain cell surface expression are well-conserved functions of human and simian immunodeficiency virus nef alleles

Trophoblast class I major histocompatibility complex (MHC) products are resistant to rapid degradation of the human cytomegalovirus (HCMV) gene products US2 and US11

Domain structure, intracellular trafficking, and beta 2-microglobulin binding of a major histocompatibility complex class I homolog encoded by molluscum contagiosum virus

The adenovirus E3-10.4K/14.5K complex mediates loss of cell surface Fas (CD95) and resistance to fasinduced apoptosis

Molluscum contagiosum virus inhibitors of apoptosis: The MC159 v-FLIP protein blocks Fas-induced activation of procaspases and degradation of the related MC160 protein

A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation

A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins

T2 open reading frame from the Shope fibroma virus encodes a soluble form of the TNF receptor

Cowpox virus encodes a second soluble homologue of cellular TNF receptors, distinct from CrmB, that binds TNF but not LT alpha

Poxvirus genomes encode a secreted, soluble protein that preferentially inhibits beta chemokine activity yet lacks sequence homology to known chemokine receptors

Murine natural killer cell activation/receptors

Ectromelia, vaccinia and cowpox viruses encode secreted interleukin-18-binding proteins

Host cell-derived complement control proteins CD55 and CD59 are incorporated into the virions of 2 unrelated enveloped viruses -human T-cell leukemia/lymphoma virus type-I (HTLV-I) and human cytomegalovirus (HCMV)

Altered expression of hostencoded complement regulators on human cytomegalovirus-infected cells

KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells

The Epstein-Barr virus BARF1 gene encodes a novel, soluble colony-stimulating factor-1 receptor

HIV-1 Nef impairs MHC class II antigen presentation and surface expression

Expression of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in Karposi's sarcoma spindle cells

E1B 19K blocks Bax oligomerization and tumor necrosis factor alpha-mediated apoptosis

The UL16-binding proteins, a novel family of MHC class I-related ligands for NKG2D, activate natural killer cell functions

Simian and human immunodeficiency virus Nef proteins use different surfaces to downregulate class I major histocompatibility complex antigen expression

Regulation of p53-dependent apoptosis, transcriptional repression, and cell transformation by phosphorylation of the 55-kiloDalton E1B protein of human adenovirus type 5

Fas-induced and tumor necrosis factor-induced apoptosis is inhibited by the poxvirus CrmA gene-product

Identification and expression of a murine cytomegalovirus early gene coding for an FC receptor

Inhibition of Bak-induced apoptosis by HPV-18 E6

Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types

The complete DNA sequence of lymphocystis disease virus

Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40

Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4(+) T cells

Interaction of the bovine papillomavirus E6 protein with the clathrin adaptor complex AP-1

Viral subversion of the immune system

CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein

Binding of hepatitis C envelope protein E2 to CD81 inhibits natural killer cell functions

Induction of Bcl-x(L) expression by human T-cell leukemia virus type 1 tax through NF-kappa B in apoptosisresistant T-cell transfectants with tax

Genome of lumpy skin disease virus

Characterization of the ectromelia virus serpin SPI-2

Vaccinia virus-infected cells release a novel polypeptide functionally related to transforming and epidermal growth factors

Encoding of a homolog of the IFNgamma receptor by myxoma virus

Extracellular enveloped vaccinia virus is resistant to complement because of incorporation of host complement control proteins into its envelope

UL40-mediated NK evasion during productive infection with human cytomegalovirus

Bovine herpesvirus 4 BORFE-2 protein inhibits fas-and tumor necrosis factor receptor 1-induced apoptosis and contains death effector domains shared with other gamma-2 herpesviruses

The murine gammaherpesvirus-68 M11 protein inhibits Fas-and TNF-induced apoptosis

Abrogation of P53-induced apoptosis by the hepatitis-B virus-X gene

Adsorption of sensitized sheep erythrocytes to HeLa cells infected with herpes simplex virus

Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction

HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals

Identification of human and mouse homologs of the MC51L-53L-54L family of secreted glycoproteins encoded by the molluscum contagiosum poxvirus

IL-18 binding and inhibition of interferon gamma induction by human poxvirus-encoded proteins

Myxoma virus expresses a TNF receptor homolog with two distinct functions

Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor

Viral interference with antigen presentation

Self-inhibition of synthesis and antigen presentation by Epstein-Barr-virus encoded EBNA1

Direct contact with herpes simplex virus-infected cells results in inhibition of lymphokine-activated killer cells because of cell-to-cell spread of virus

Apparent effectiveness of natural killer cells vis-à-vis retrovirus-infected targets

Target protease specificity of the viral serpin CrmA -Analysis of five caspases

A mouse cytomegalovirus glycoprotein retains MHC class I complexes in the ERGIC/cis-Golgi compartment

HIV-1 Tat inhibits human natural killer cell function by blocking L-type calcium channels

Human herpesvirus 6 open reading frame U83 encodes a functional chemokine