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Viral strategies for evading antiviral cellular immune responsesof the host

Alexandre Iannello, Olfa Debbeche, Elodie Martin, Lynda Habiba Attalah, Suzanne Samarani,and Ali Ahmad1

Laboratory of Immunovirology, Ste-Justine Hospital Research Center, Department of Microbiolgy and Immunology,University of Montreal, Quebec, Canada

Abstract: The host invariably responds to infect-ing viruses by activating its innate immune systemand mounting virus-specific humoral and cellularimmune responses. These responses are aimed atcontrolling viral replication and eliminating the in-fecting virus from the host. However, viruses haveevolved numerous strategies to counter and evadehost’s antiviral responses. Providing specific exam-ples from the published literature, we discuss inthis review article various strategies that viruseshave developed to evade antiviral cellular re-sponses of the host. Unraveling these viral strate-gies allows a better understanding of the host-pathogen interactions and their coevolution. Thisknowledge is important for identifying novel mo-lecular targets for developing antiviral reagents.Finally, it may also help devise new knowledge-based strategies for developing antiviral vaccines.J. Leukoc. Biol. 79: 16–35; 2006.

Key Words: antigen presentation � CTL � NK cells � MHC antigens� viral infections

INTRODUCTION

Viruses and their hosts have coevolved for millions of years.During this coevolution, the hosts have equipped themselveswith an elaborate immune system to defend themselves fromthe invading viruses and other pathogens. The viruses, on theirpart, have developed many strategies to evade host’s antiviralimmune responses. These strategies, which have allowed vi-ruses to replicate and persist successfully in the host, will bediscussed in this article. We will begin this discussion with abrief overview of the antiviral immune responses of the host.

ANTIVIRAL IMMUNE RESPONSESOF THE HOST

The immune system can be defined as an overall coordinationof the biological mechanisms involved in the integrity andprotection of the host from malignancy and infectious agentssuch as viruses. The system can be divided arbitrarily into twomajor parts: the innate and adaptive. The principal immuneeffector cells of the innate immune system are monocytes/

macrophages, dendritic cells (DC), natural killer (NK) cells,and NK-T cells. These effector cells recognize pathogen-asso-ciated molecular patterns, e.g., viral proteins, CpG DNA, ordouble-stranded viral RNA, via a variety of so-called patternrecognition receptors, which include Toll-like receptors, NKcell receptors, and mannose-binding receptors [1, 2]. Thesecells then release a variety of proinflammatory cytokines andchemokines, which recruit inflammatory cells to the site ofinfection and initiate inflammation and antiviral immune re-sponse. These soluble mediators also activate macrophages,NK cells, and DC. Activated DC express CC chemokine re-ceptor 7 and other adhesion molecules and migrate to lymphnodes to present antigen to T and B cells. Viral infections areusually accompanied by NK cell activation. Activated NK cellskill virus-infected cells and serve as an immediate source ofinterferon-� (IFN-�). The killing of virus-infected cells is animportant danger signal to initiate immune response. The NKcell-secreted IFN-� plays an important role in inducing aneffective antiviral immune response. An important event is theinduction of type I (� and �) IFN. Although almost all celltypes can produce these IFN, a specialized cell type, precursorplasmacytoid DC, produces 1000-fold more of these cytokinesand is called the natural IFN-producing cell [3, 4]. IFNs alsoincrease expression of major histocompatibility complex(MHC) class I and II antigens and of costimulatory moleculeson the surface of so-called antigen-presenting cells (APC). Theprofessional APC include DC, macrophages, and B cells. Theypresent virus-derived antigenic peptides to naıve CD8� Tcells and CD4� T cells in association with MHC class I andclass II antigens, respectively (Fig. 1). This antigen presenta-tion is a critical step in the induction of virus-specific immu-nity by the adaptive immune system. Activation of the innateimmune system plays an instructive role (adjuvant effect) forthe induction of virus-specific, adaptive immune responses. Ingeneral, exogenous viral particles and viral antigens are phago-cytosed and/or endocytosed by APC. They are then degraded inlysosomes, and immunogenic peptides are presented in asso-ciation with MHC class II antigens to naıve CD4� T cells [5].The virus-specific CD4� T cells provide essential help for the

1 Correspondence: Laboratory of Immunovirology, Ste-Justine Hospital Re-search Center, 3175 Cote Ste Catherine, Montreal, Quebec, H3T 1C5, Canada.E-mail: [email protected]

Received July 20, 2005; revised August 9, 2005; accepted August 18, 2005;doi: 10.1189/jlb.0705397.

16 Journal of Leukocyte Biology Volume 79, January 2006 0741-5400/06/0079-0016 © Society for Leukocyte Biology

induction of antiviral CTL, antibodies, and memory T cells.The T helper cells (Th) are further divided into two types: TH-1and TH-2 [6]. The two types of the Th cells differ in theexpression of their cytokine profiles. The TH-1 and TH-2 cellsproduce and differentiate in response to IFN-� and interleukin(IL)-4, respectively. The role of IFN-� in the differentiation ofTH-1 cells, however, is indirect, i.e., by inducing the produc-tion of IL-12 from macrophages and DC. In addition to IFN-�,the TH-1 cells produce IL-2 and TNF-�. They promote theproduction of immunoglobulin G2a (IgG2a) in mice and IgG1and IgG3 in humans and activate macrophages and CD8�CTL. These responses are essential for clearing intracellularpathogens. The TH-2 cells produce IL-4, IL-5, IL-9, and IL-13and promote the production of IgG1 and IgE in mice and IgG4and IgE in humans. They inhibit macrophage activation andpromote differentiation and growth of mast cells and eosino-phils. These TH-2 cell-induced allergic inflammatory re-sponses are important in clearing extracellular parasites. Effi-cient induction of virus-specific type 1 CD4� helper responsesis believed important for inducing effective antiviral immuneresponses in the host. Studies from several viruses have dem-onstrated an essential role of virus-specific CTL in controlling

viral replication [7, 8]. For the generation of CTL, APC presentantigenic peptides derived from the endogenously expressedviral proteins in association with classical MHC class I mole-cules to naıve CD8� T cells. These CD8� T cells expand anddifferentiate into virus-specific effector CTL. The virus-specificCD4� Th cells also play an important role in the generation ofCTL and virus-specific memory T cells. The CTL kill virus-infected cells by recognizing their cognate virus-derived pep-tides in association with MHC class I molecules. They killthem by exocytosing several cytotoxic molecules, e.g., perforin,granzymes, and granulysin, in the immune synapse formedbetween CTL and the target cell. Fas/FasL and TRAIL/DRinteractions may also play a role in this killing. The generationof virus-specific memory T cells is important for an efficientvirus-specific anamnestic response, a criterion desired for an-tiviral vaccines.

NK cells and macrophages also kill virus-infected cells inassociation with virus-specific antibodies. NK cells kill anti-body-coated, virus-infected cells via antibody-dependent, cell-mediated cytotoxicity (ADCC). Virus-specific ADCC plays asignificant role in killing virus-infected cells, especiallyagainst human immunodeficiency virus (HIV) and herpesvi-

Fig. 1. APC present viral antigens to naive T cells. The APC present peptides from endogenously produced viral proteins via MHC class I to CD8� T cells andfrom exogenous viral proteins via MHC class II to CD4� T cells. They also activate NK cells. If the APC express death receptor (DR) ligands, e.g., tumor necrosisfactor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL), they may kill the interacting immune cells instead of priming and activating them.CTL, Cytotoxic T lymphocyte; TNFR, TNF receptor; TRAILR, TRAIL receptor; TCR, T cell receptor; ER, endoplasmic reticulum; MIIC, MHC class II loadingcompartments.

Iannello et al. Viral immune evasion strategies 17

ruses [9]. Macrophages and polymorphonuclear leukocytes canengulf antibody-coated pathogens as well as virus-infectedcells and/or kill them via reactive oxygen species, nitric oxide,and activated caspases.

NK cells may also kill virus-infected cells without help fromantibodies [10]. These cells, however, usually do not recognizeany viral antigen or viral peptide per se. Their effector functionis controlled by a complex system of inhibitory and activatingNK cell receptors and coreceptors. They kill target cells unlessinhibited by the engagement of inhibitory receptors by theircognate ligands on the target cells. The most important inhib-itory receptors include killer cell Ig-like receptors (KIR),NKG2/CD94A, and Ig-like transcripts (ILT), which bind toclassical and nonclassical MHC class I antigens; also calledhuman leukocyte antigen (HLA)-A, -B, -C, -E, and -G (Table1). It is noteworthy that most of the KIR recognize HLA-C andinhibit NK cells. A down-regulation of the MHC antigens onthe surface of virus-infected cells usually makes them suscep-tible to NK cell-mediated killing [10, 11]. Despite their differ-

ent mechanisms of recognition of virus-infected cells, NK cellsand CTL represent the most important cytolytic cells leading tothe elimination of tumor and virus-infected cells from the host.Furthermore, both cell types secrete cytokines such as IFN-�and TNF-�, which interfere with viral replication without caus-ing cell death [12].

VIRAL IMMUNE EVASION STRATEGIES

The purpose of an elaborate system of innate and adaptiveantiviral immune mechanisms is to seek out and destroy vi-ruses and virus-infected host cells. Viruses have developedvarious strategies to subvert host’s antiviral responses to ensuretheir own replication and survival. In recent years, a lot of newinformation has become available about the biology of manydifferent viruses, which required an update on existing reviewson the subject [13–17]. These strategies are discussed below.

TABLE 1. Human NK Cell Receptors, Coreceptors, Their Ligands, and Functions

Receptors Ligand Function

A. Natural cytotoxicity receptors:1. NKp46 Haemagglutinin A2. NKp44 Haemagglutinin A3. NKp30 pp65 of HCMV A

B. CD94/NKG2 family:1. NKG2D L MICA, MICB, ULBP1–4 Cos2. NKG2D S MICA, MICB, ULBP1–4 A3. CD94/NKG2A HLA-E I4. CD94/NKG2C, E HLA-E A

C. KIR family*:1. KIR2DS1 HLA-C Lys.p80 A2. KIR2DS2 HLA-C Asn.p80 A3. KIR2DS4 HLA-C? A4. KIR2DS3, 5 ? A5. KIR2DS6 ? A6. KIR3DS1 ? A7. KIR2DL1 HLA-C Lys.p80 I8. KIR2DL2/3 HLA-C Asn.p80 I9. KIR3DL1 HLA-B Bw4 (Ile.p80) I

10. KIR3DL2 HLA-A3, ? I11. KIR2DL4 HLA-G A12. KIR2DL5 ? I13. KIR2DL7 ? ID. ILT family:ILT 1–10 HLA-A, -B, -C, -G A or ICoreceptors:1. CD11a/C18 (LFA-1) CD54 (ICAM-1) A, Cos, Con2. CD2 (LFA-2) CD58 (LFA-3) CD48 A, Cos, Con3. CD8 MHC class I Cos4. CD69 ? Cos5. CD56 Self Homotypic adhesion6. CD16 (Fc�RIIa) Fc regions of IgG, IgE A7. CD244 (2B4) CD48, CD2 (weakly) A or I8. NTB-A ? A or I9. NKR-P1 Ocil A or I

10. DNAM-1 CD155, CD112 Cos

HCMV, Human cytomegalovirus; MICA/B, MHC class I heavy chain-like protein A/B; ULBP1-4, UL-16-binding protein 1–4; Lys, lysine; Asn, asparagine;LFA-1, lymphocyte function antigen-1; ICAM-1, intercellular adhesion molecule-1; Fc�RIIa, Fc receptor for IgGIIa; NTB-A, NK-T and -B cell antigen; NKR-P1,NK cell receptor protein 1; Ocil, osteoclast inhibitory lectin; DNAM-1, DNAX accessory molecule 1. The letters denote: A, Activation; Cos, costimulation; I,inhibition; Con, conjugate formation with target cells. * The LY 49 genes represent functional homologues of KIR in mice.

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Interference with antigen presentation via MHCclass I and induction of antiviral immuneresponses

As APC present virus-derived antigenic peptides in associationwith MHC class I antigens to prime antiviral CTL, virusesinterfere with this antiviral response by down-regulating theexpression of MHC class I molecule on the surface of APC. Thevirus-specific CTL recognize virus-derived antigenic peptidesin association with MHC class I antigens. A decreased expres-sion of these antigens on the surface of the virus-infected cellsprevents their recognition and killing by the CTL. As shown inFigure 2 and summarized in Table 2, viruses use manydifferent strategies for this purpose. They may do so by thefollowing:

Repressing transcription of MHC genes

The Tat protein encoded by HIV-1 is a transcriptional activatorof the viral long terminal repeat. However, it can also repressseveral cellular gene promoters [18]. The activating and re-pressing functions reside in distinct domains of the protein.The repressive domain (at the C terminus) can associate withthe transcription factor IID complex and inhibit the histoneacetyl transferase activity of the TFII250 factor, causing re-pression of several genes involved in the induction of immuneresponse, e.g., MHC class I and �2m [18–20]. The E5 and E7proteins of the bovine and human papillomaviruses are onco-

proteins, which are expressed early in the viral life cycle in theGolgi complex (GC) and ER. They reduce MHC class I mRNAlevels with a certain degree of specificity as well as retain MHCantigens in the GC and ER [21, 22]. The E1A early protein ofthe oncogenic adenovirus Ad12 also inhibits transcription ofall components of the MHC class I pathway.

Fig. 2. Interference of viral proteins with antigenpresentation via MHC class I. The endogenous pro-teins are degraded by 26S proteasome, and thepeptides are actively transported into ER for load-ing onto nascent MHC heavy chains, which areassociated noncovalently with �2 microglobulin(�2m). The peptide-loading complex (PLC) com-prises transporter associated with antigen process-ing (TAP)-1, TAP-2, tapasin, ER-57, and calrecti-culin. The peptide-loaded (mature) MHC antigensthen exit ER to the cell surface via the Golgi net-work. The viral proteins and the steps, at which theyinterfere with this antigen presentation pathway, areshown in red. EBNA-1, Epstein-Barr virus (EBV)nuclear antigen-1; HSV-1, Herpes simplex virustype 1; MHV-68, murine �-2 herpesvirus 68;KSHV, Kaposi sarcoma herpesvirus; MCMV, mu-rine cytomegalovirus.

TABLE 2. Viral Strategies to Down-Regulate MHC Antigens*

A. MHC class I1. Decreasing the transcription of MHC class I genes, e.g., HIV

Tat, Papillomavirus E5.2. Blocking the TAP function and the transport of peptides into

ER, e.g., HSV-1 ICP47, HCMV US6.3. Inhibiting proteasomal degradation of the viral protein, e.g.,

EBV EBNA-1.4. Inhibiting intracellular transport of MHC class I heavy chains,

e.g., HIV Nef, HCMV US11.5. Ubiquitinylating and degrading the MHC antigens, e.g.,

KSHV K3 and K5.B. MHC class II

1. Decreasing the transcription of MHC class I genes, e.g., HIVTat, Papillomavirus E5.

2. Interfering with peptide loading in the MHC class II peptide-loading compartments, e.g., HSV-1 gB, HIV Nef.

3. Enhanced proteasomal degradation, e.g., HCMV US2.4. Interfering with TCR-MHC class II interactions, e.g., EBV

g42.

* Each virus usually uses multiple strategies.


Inhibiting proteasome-mediated degradation and generationof peptides

The expression of MHC class I antigens on the cell surfacerequires the availability of peptides in the ER. The peptidesare produced in the cytosol via proteasomal degradation of viralproteins (Fig. 2). Many viruses have developed the strategy ofinhibiting this degradation and limiting the pool of availablepeptides. For example, the EBV encodes a nuclear protein,EBNA-1, which is essential for replication of the viral episomein dividing virus-infected/transformed cells. The protein con-tains a glycine-alanine-rich (GAr) domain, which inhibits itsdegradation by the 26S proteasome, thus reducing the pool ofEBNA-1-derived peptides that could be presented with MHCclass I antigens on the cell surface [23]. Furthermore, the GArmotif also inhibits translation of the EBNA-1 mRNA in cis, andthis effect can be distinguished from its effect on proteasomaldegradation. By limiting its production at the translationallevel, EBNA-1 effectively decreases synthesis of defectiveribosomal products (DRIPs). It is noteworthy that DRIPs un-dergo enhanced degradation and are the major source of pep-tides. Thus, EBV translates a functional level of EBNA-1needed for its replication without antigenic presentation by theMHC class I, which could lead to the generation of CTL againstthis viral protein as well as recognition of the infected cells byvirus-specific effector CTL [23].

Blocking TAP functions

Many viruses can inhibit the loading of antigenic peptides ontoMHC class I molecules by blocking functions of TAP [24],which translocates peptides generated in the cytosol by pro-teasomal degradation into ER for loading onto nascent MHCclass I molecules. As stated earlier, without peptides, MHCclass I molecules cannot fold properly and be expressed on thecell surface. TAP exists as a heterodimeric complex compris-ing TAP-1 and TAP-2 and is an essential component of thePLC. The other components of the complex include Tapasin,MHC class I � chain, calreticulin, Erp57, and �2m (Fig. 2).Tapasin forms a bridge between TAP and MHC class I andedits quality of the MHC-bound peptides. Calrecticulin mon-itors proper glycosylation pattern of the nascent MHC mole-cules specifically recognizing N-linked glycans, and Erp-57 isa thiol oxido-reductase, which isomerizes intrachain S–Sbonds. Many viruses encode proteins that can interfere withTAP functions and hence, with the translocation of peptidesinto the ER. The bovine herpesvirus-1-encoded proteinUL49.5 is a potent inhibitor of TAP. It inhibits TAP byinducing a conformational arrest of the transporter as well as bytargeting TAP to proteasomal degradation [25]. It is noteworthythat UL49.5 homologues are found in two other varicellovi-ruses: pseudorabies virus and equine herpesvirus-1. The ade-novirus early transcription unit-3 (E3)-19K and the HSV-1protein infected cell peptide 47 (ICP47) can also inhibit pep-tide translocation into ER by blocking functions of TAP lead-ing to a decrease in cell surface expression of MHC class Iantigens [26, 27]. The ICP47 binds to the cytosolic side of TAPand blocks its function, whereas E3-19K binds TAP and MHCand acts as a competitive inhibitor of tapasin. The HCMV-encoded protein US6 can transiently associate itself with theTAP complex [28]. This association inhibits the peptide trans-

location toward the ER and prevents maturation and presen-tation of MHC class I at the cell surface [29–32]. It has alsobeen demonstrated that the US6 binds to the luminal side ofTAP and allosterically inhibits its ATPase activity [33, 34].The disruption of TAP function, however, does not affectexpression of HLA-E, a nonclassical MHC class I molecule,which binds peptides derived from MHC class I signal se-quences and confers protection from NK cell-mediated lysis[35].

Degradation of PLC and MHC class I antigens

Many viruses can interfere with antigen presentation via MHCclass I by degrading the PLC. The HCMV unique short regiongenes encode at least four proteins US2, US3, US6, and US11.Each of them can independently down-regulate the expressionof MHC class I antigens on the surface of the virus-infectedcells. The US2 and US11 induce a rapid degradation of thenascent HLA class I molecules during their synthesis [36, 37].The US2 binds to the MHC class I molecules during theirglycosylation, leading to their retrograde transport to the cyto-plasm and the degradation of the whole complex [38]. It is inter-esting that none of these proteins degrades the HCMV-encodedMHC homologue UL18. The latter protein forms heterotrimericcomplexes with �2m and endogenous peptides, providing protec-tion from NK cell-mediated lysis and inhibiting macrophage ac-tivation via its interaction with an inhibitory receptor ILT-2,expressed on NK cells and macrophages [39–42]. The homologuemay also sequester �2m and inhibit MHC class I expression onthe cell surface. Crystallographic studies have shown that US2associates with HLA-A2 at the junction of the peptide-bindingregion and the �3 domain, a binding surface that allows US2 tobind the MHC molecule independently of the peptide sequenceand to exert its down-regulatory effects [43].

Poxviruses and �-herpesviruses share the K3 family of viralimmune evasion proteins (immunoevasins), which possess anamino-terminal plant homeodomain/leukemia-associated pro-tein domain or more specifically, a really interesting new genewith conserved cysteins and histidine residues (RING-CH)domain, followed by two transmembrane domains. The K3family proteins have ubiquitin (Ub) ligase activity [44, 45].They inhibit the surface expression of glycoproteins, such asMHC class I heavy chains, B7.2, ICAM-1, or CD95, by tar-geting them to Ub-directed proteasomal degradation. The hu-man homologues of these immunoevasins are the membrane-associated RING-CH (MARCH) proteins, which have func-tional similarity with K3 proteins. This suggests that these viralimmune evasion proteins have been derived from the cellularMARCH proteins. The MARCH proteins regulate endocytosisof cell surface receptors via ubiquitinylation [46]. The KSHVproteins K3 and K5 [also called modulator of immune recog-nition (MIR)-1 and -2, respectively] as well as the MHV-68protein MK3 prevent the surface expression of MHC class Imolecules [47–49]. MIR-1 and MIR-2 also down-regulate thesurface expression of CD-1 [50], a family of antigen-presentingmolecules, which are distantly related to MHC class I moleculesand present lipid and glycolipid antigens to T and NK-T cells. Theprotein MK3 resides in the ER membrane, where it binds to andubiquitinylates the cytoplasmic tails of newly synthesized MHCclass I heavy chains while bound to peptides in the PLC,


leading to their proteasome-dependent degradation [51]. It canalso degrade Tapasin and TAP in a RING finger-dependentmanner [52]. Studies about a model for the interaction of MK3with MHC-I and the PLC have shown that MK3 interacts withTAP-1 and -2 via their C-terminal domains and with class Imolecules via their N-terminal domains [53]. It is interestingthat the K5-mediated down-regulation of MHC class I mole-cules does not render the virus-infected cells susceptible to NKcell-mediated lysis, as it also down-regulates the expression ofICAM-1 and B7.2 on the infected cells. These molecules act asligands for NK cell-mediated cytotoxicity. De novo expressionof B7.2 and ICAM-1 in the K5-expressing cells restores theirsensitivity to NK cells [54]. Furthermore, unlike K3, whichdown-regulates all MHC allotypes, K5 only degrades HLA-Aand -B but not HLA-E, and the effect on HLA-C is weak [54].The myxoma virus (a poxvirus) ER resident protein M153Rdown-regulates MHC class I and has been shown to haveUb-ligase activity in vitro [55].

Viruses have evolved strategies to affect intracellular traf-ficking of MHC class I antigens and cause its retention insidethe ER. The HCMV US3 protein associates itself with the MHCclass I heavy chain/�2m complex and causes its retention inthe ER without interfering with the maturation [56, 57] and themovement of the complex through the Golgi apparatus [58, 59].MCMV has been shown to encode three genes, m152, m6, andm4, which are involved in the interference with MHC-I expres-sion and/or recognition. The m152 blocks the export of MHC-Ifrom a pre-Golgi apparatus, whereas m6 directs it to lysosomaldegradation (Fig. 2). The MCMV m4 encodes a glycoprotein,gp34, which is expressed on the cell surface in a complex withMHC class I. It does not inhibit the surface expression of theclass I but inhibits its recognition by H-2Kb-restricted CTL.Thus, m4 acts as a viral CTL evasion protein without affectingexpression of MHC-1. It is relevant to mention here that them152/gp40-mediated inhibition of H-2Db is complete, but thatof H-2Kb is partial. Therefore, MCMV needed m4 as an addi-tional strategy to inhibit Kb recognition by CTL clones [60].Indeed, m152 appears sufficient to abolish Db-restricted pre-sentation in the virus-infected primary macrophages, but m4,m6, and m152 are required to escape the recognition of virus-infected cells by Kb-restricted CTL [61].

The adenovirus E3-19K protein can also block cell surfaceexpression of MHC class I by specifically preventing theirterminal glycosylation, correct folding, and export from ER[62]. The human herpesvirus 7 (HHV7) protein U21 associateswith the MHC class I inside the ER and directs its traffictoward the lysosomes for degradation [63].

Differential down-regulation of MHC class I antigens

A global indiscriminate down-regulation of MHC class I mol-ecules on the surface of virus-infected cells may prevent theirrecognition from virus-specific CTL. However, this strategyalso renders the infected cells susceptible to NK cell-mediatedkilling. As stated earlier, MHC class I molecules, particularlyHLA-C, act as ligands for inhibitory NK cell receptors, e.g.,KIR. A loss or a decreased expression of these HLA alleles onthe surface of virus-infected cells results in a loss of inhibitionof NK cells. To evade killing by NK cells and virus-specificCTL, many viruses have evolved strategies to differentially

down-regulate MHC class I molecules. More specifically, theydown-regulate expression of HLA-A and -B, which mainlypresent viral epitopes to CTL, but not the expression of HLA-Cand HLA-E, which act as ligands for inhibitory NK cell recep-tors. HIV-1 uses this strategy via Nef protein, which bindshypophosphorylated cytoplasmic tails in early forms of theMHC class I antigens in the ER and redirects them from thetrans-Golgi network (TGN) to endosomal degradation [64].Indeed, studies have shown that all Nef domains (the N-terminal � helix, polyproline, acidic, and oligomerization do-mains) are involved in this association [65]. Nef interactsselectively with the intracellular tyrosine motifs of differentHLA-A and HLA-B allotypes [66]. However, the HLA-C andHLA-E do not have these tyrosine motifs and are not targetedby Nef [67], which interacts with the � subunit of the cellularadaptor protein (AP) complex and recruits it to the MHCcytoplasmic tails. This interaction with AP causes endocytosisand retrograde trafficking of the MHC molecules from the cellsurface. They accumulate in clathrin-coated vesicles and aretargeted to degradation. However, the Nef mutants, which donot interact with AP, can also down-regulate MHC expression[64, 65]. Piguet et al. [68] have shown that Nef-mediateddown-regulation of the MHC antigens involves interaction be-tween the acidic domain of Nef and phosphofurin acidic clustersorting (PACS)-1, a molecule that localizes the cellular proteinfurin to the trans Golgi network (TGN). According to theirmodel, Nef acts as a connector between the cytoplasmic tails ofthe MHC antigens and PACS-1-dependent protein-sortingpathway. In T cells, however, Nef mediates down-regulation ofthe MHC molecules via disrupting its secretory pathway fromthe TGN to the cell surface, whereas in non-T cells, theseeffects of Nef on the transport of the MHC molecules to the cellsurface are less pronounced [64, 69]. Overall, Nef inhibitsexpression of HLA-A and -B alleles on the cell surface andprotects the infected cells from CTL-mediated lysis [66, 69–71]. Indeed, the effects of Nef on MHC surface expression havebeen shown to be important for the progression of the HIVinfection toward AIDS [72, 73].

As mentioned above, the KSHV proteins K3 and K5 havethe capacity to internalize the MHC class I antigens by Ub-directed degradation from the cell surface. The two proteinsdiffer in their specificity for different MHC alleles. The K5down-regulates HLA-A and -B efficiently but not HLA-C and-E. The K3, conversely, down-regulates all MHC class I allo-types. The K5 also down-regulates the surface expression ofICAM-1 and B7.2 in the virus-infected cells. This differentialdown-regulation of the MHC molecules as well as of ICAM-1and B7.2 confers resistance to NK cell-mediated lysis to thevirus-infected, MHC-deficient cells [54, 74].

It seems that many viruses encode proteins to down-regulatethe expression of MHC class I molecules from the surface ofthe infected cells (Fig. 2; Table 2). They do so primarily toevade host’s antiviral CTL responses. However, certain virusesmay in fact increase the expression of these molecules on thesurface of the infected cells, at least in the early phase of theinfection, when NK cells are activated. For example, flavivi-ruses stimulate TAP activity by up to 50% [75]. More specif-ically, the Hepatitis C virus (HCV) core protein was shown toactivate TAP functions via p53 induction [76]. This enhances


the TAP-dependent peptide import into the ER lumen andincreases the surface expression of MHC class I antigens. Thevirus-infected cells consequently become more resistant to NKcell-mediated killing. Activated NK cells seem to be importantin limiting viral replication, at least in the early phases of theinfection before the generation of virus-specific CTL and an-tibodies.

Down-regulating the expression of MHC class IIon the surface of virus-infected cells

The expression of MHC class II molecules on the surface ofprofessional APC is essential for presentation of foreign anti-genic peptides to CD4� T lymphocytes. This presentationresults in the generation of antigen-specific CD4� Th cells.The professional APC-like macrophages, DC and B cells takeup exogenous viral proteins by phagocytosis or endocytosis.These cells generate antigenic peptides by protease action inendosomal compartments that are presented by MHC class IImolecules, encoded by three different loci (HLA-DP, -DQ, and-DR). The heterodimeric �/� chain constituting the MHC classII is strongly associated with the invariant chain (Ii) in the ERin a nonameric complex and represents an immature MHC-IIform. The MHC-II �/�/Ii nonameric complexes are targeted tothe MIIC, which are late endosome/lysosome-like compart-ments. During this transport, proteases present in the endo-somes partially cleave the invariant chain, via a series ofdefined cleavage intermediates, to generate class II-associated

Ii peptide, which occupies the peptide-binding groove of theMHC class II until it is exchanged by an antigenic peptide inthe MIIC. This process of peptide loading is catalyzed byHLA-DM and -DO (in B cells) inside the MIIC [77–80]. Thisexchange leads to the constitution of a stable heterotrimericMCH class II peptide complex, mature MHC class II, which cannow reach the cell surface. By inhibiting the MHC class IIantigenic presentation at different levels, viruses interfere with thegeneration of virus-specific CD4� T cells and hence, with theinduction of an effective antiviral cellular immune response.

Viruses encode proteins that may interfere with expres-sion of MHC class II antigens (by down-regulating theirtranscription and/or by disrupting their normal traffic withinthe cells); loading of peptides onto these antigens; and theirpresentation to naıve CD4� T cells by disrupting the inter-action between MHC class II antigens and TCR (Fig. 3,Table 2). This is a relatively less-studied aspect of viralimmune evasion. However, in recent years, many viral pro-teins have been shown to interfere with antigen presentationvia MHC class II pathway.

At the transcriptional level, the HIV-1 Tat protein competeswith the cellular transactivator MHC class II transactivator(CIITA) and represses the expression of genes encoding for theMHC class II antigens. The factor is required for transcrip-tional activation of MHC class II genes. Tat competes withCIITA for the cyclin T1/CD9 complex by binding to the samesite on the cyclin [20].

Fig. 3. Viruses use multiple strategies to inhibit antigen presentation to T cells. A global view of the strategies for inhibiting antigen presentation via MHC classI and class II molecules is shown. The boxes indicate the viral strategies and give examples of the viruses and their proteins, which use the strategy. SIV, Simianimmunodeficiency virus; E3-RID, E3-receptor internalization and degradation.


The adenovirus E1A protein can efficiently inhibit IFN-�-induced up-regulation of HLA class II genes by inhibitinginteraction between the cyclic AMP response element-bindingprotein (CREB)-binding protein (CBP) and the CIITA (ref. [81],reviewed in ref. [82]). The IFN-mediated effects on the MHC IIexpression are important for the induction of an effectiveantiviral immune response.

Another way to subvert the antigen presentation is to alterthe intracellular trafficking of the class II antigens. In HSV-infected cells, the viral glycoprotein B competes with the Iichain for binding with HLA-DR molecules. In addition, it alsoassociates with HLA-DM. It disturbs intracellular trafficking ofMHC class II and prevents them from reaching the cell surface[83, 84]. The HIV Nef also impairs the membrane expressionof mature (peptide-loaded) MHC class II molecules and pro-motes the surface expression of their immature (peptide-lack-ing) forms. The Nef expression induces a marked accumulationof multivesicular bodies (MVB) containing Nef, MHC class II,and high amounts of Ii [85, 86]. It is interesting that HIV-1recruits MVB machinery for budding in macrophages. TheHCMV US2 and US3 proteins are also involved in the subver-sion of antigen presentation to CD4� T cells via MHC class II.The two proteins collaborate to achieve this end [87]. US2causes rapid retrotranslocation of class II proteins DR-� andDM-� from the ER, followed by their proteasome-mediateddegradation [88]. US3 binds to the newly synthesized MHCclass II �/� complexes in the ER and reduces their associationwith Ii. This complex moves normally to the Golgi apparatusbut is not sorted efficiently to the MIIC, leading to a reductionof the peptide-loaded, mature MHC class II complexes on thecell surface and of their recognition by CD4� T cells [89].

Prevention of the MHC class II-TCR interaction

The EBV lytic cycle protein gp42 is a type II transmembraneglycoprotein, which binds HLA-DR. This binding is essentialfor viral entry into DR-positive B cells. The viral protein alsoassociates with MHC class II molecules at various stages oftheir maturation, e.g., immature �-�-li heterotrimers and ma-ture �-�-peptide complexes, and inhibits antigen presentationto CD4� T cells. It is interesting that a soluble form of gp42is generated by proteolytic cleavage in the ER of the virus-infected cells. The protein is secreted and inhibits HLA classII-restricted antigen presentation to T cells by physically hin-dering the MHC class II-TCR interactions. The transmembraneand soluble forms of the protein are expressed in the EBVgenome-positive Burkitt’s lymphoma cells during lytic infec-tion of the virus [90, 91]. Another example in this case is theenvelope protein of HIV-1, gp120, which binds CD4 andinterferes with CD4-MHC class II interactions [92].

By down-regulating the expression ofcostimulating molecules

A variety of costimulatory molecules is expressed on the sur-face of professional APC and other host cells. These moleculesinteract with their cognate ligands on immune cells. Thisinteraction plays an essential role in the presentation of viralantigens to T cells and B cells and for the induction of aneffective antiviral cellular immunity. Costimulation is also

important for the efferent or effector phase of the immuneresponse. For example, stimulation of CD4� T cells via anti-gen alone (MHC class II molecules loaded with the receptor-specific peptides) would not proliferate and produce IFN-�unless costimulated via B7.1 and CD28 interactions. Instead,they would rather become anergic or undergo apoptosis. Sim-ilarly, IL-2-activated NK cells would undergo apoptosis ifstimulated only via CD16. Many viruses inhibit host’s antiviralimmune responses at the inductive and effector phases bydown-regulating the expression of costimulatory molecules onhost cells. For example, the KSHV-K5 down-regulates surfaceexpression of the costimulatory molecules ICAM-1 and B7.2 onthe surface of virus-infected cells [93, 94]. The Myxomavirushomologue of the K5, M153R, is also a Ub ligase. It targetsMHC class I antigens and CD4 and internalizes and redirectsthem to proteasomal degradation. The M153R-mediated deg-radation is dependent on the presence of lysine residues in thecytoplasmic tails of the target proteins [55, 95]. The adenovirusoncoprotein E1A decreases the expression of another adhesionmolecule lymphocyte function-associated antigen-3 on the sur-face of Ad5- and Ad12-transformed cells [96]. It is noteworthythat Nef, Vpu, and Gp160 of HIV-1 reduce surface expressionof CD4 and CD28 on the virus-infected cells. Therefore, HIV-infected cells cannot provide proper costimulation when theyinteract with virus-specific T cells [71, 85].

The induction of a virus-specific CTL response to HCMVand MCMV represents the main and most efficient effectorfunction for the control of these pathogens [97–100]. TheHCMV main tegument protein pp65 and the immediate earlyprotein-1 (IE1) are the major targets for the antiviral CTLraised against HCMV-infected cells [97]. The pp65 has kinaseactivity. It phosphorylates and inhibits presentation of IE pro-teins, such as pp72, to CD8� T cells via MHC class I antigens[101]. The pp72 is an essential viral transcription factor. It isinteresting that the HCMV-specific CTL response is dominatedby the pp65. This protein was recently shown to act as a ligandfor NKp30, an activating NK cell receptor. The binding of theprotein to the receptor causes dissociation of the receptor-associated signaling component, the � chain [102], which actsas a signaling component for several other activating receptorsfound on the surface of NK and T cells. Thus, the protein maycause a general immunosuppression in the infected host.

Evading host’s NK cell responses

NK cells are a population of bone marrow-derived, low-density,large granular lymphocytes. They constitute 10–15% of thelymphocytes in blood [103]. They can kill certain virus-in-fected and tumor cells without prior activation and sensitiza-tion. Apart from killing virus-infected cells, NK cells play animportant role in immune regulation by secreting immunolog-ically important cytokines and chemokines, e.g., includingIFN-�, TNF-�, macrophage-inflammatory protein-1� (MIP-1�), and MIP-1�. The NK cell-secreted IFN and TNF-� mayalso control viral replication by noncytolytic mechanisms. NKcells and mature DC reciprocally activate each other. As statedearlier, NK cells are usually activated in early phases of a viralinfection. Activated NK cells are important in killing virus-infected cells, especially before the generation of virus-specificCTL and antibodies. Unlike T and B cells, which express


well-defined, clonally distributed antigen receptors, NK cellsactivity is controlled by a diverse array of activating andinhibitory receptors and coreceptors, which bind different li-gands present on the surface of a target cell and send activatingand inhibitory signals to the NK cell. The balance between theinhibitory and activating signals determines whether the NKcells would kill the target cell or be inhibited from killing it. Inrecent years, a great deal has been learned about these recep-tors and their ligands [11, 104]. The known NK cell receptorsand coreceptors as well as their ligands are given in Table 1.The most important ligands, which bind inhibitory receptors onNK cells and inhibit their activity, are MHC class I antigens,especially HLA-C and -E. Most body cells and tumor cellsusually express ligands for some activating NK cell receptors.NK cells would kill these cells by default unless they areinhibited by the engagement of their inhibitory receptors. Thepresence of MHC class I antigens on the surface of a cellusually makes it resistant to NK cell-mediated killing.

As NK cells could play an important role in controlling virusreplication, viruses have evolved many strategies to evadehost’s NK cell responses (see Table 3).

As stated earlier, viruses usually down-regulate the expres-sion of MHC class I on the surface of the infected cells toescape antiviral CTL. However, this MHC down-regulationusually makes them susceptible to NK cell-mediated killing.Many viruses, therefore, have evolved the strategy to differen-tially down-regulate MHC class I antigens. They down-regulateHLA-A and -B but not HLA-C and -E. As HLA-A and -Bmainly present virus-derived antigenic peptides to CTL, theirdown-regulation protects virus-infected cells from CTL-medi-ated killing. Conversely, HLA-C and -E mainly act as ligandsfor inhibitory NK cell receptors by maintaining their normalexpression on the surface of virus-infected cells; viruses tendto maintain their resistance to NK cells. This way, these virusescan evade CTL and maintain resistance of the virus-infectedcell to NK cells.

The viruses may also evade NK cell responses by increasingthe expression of HLA-E. For its expression on the cell surface,this nonclassical HLA molecule needs peptides derived from

the signal sequences of HLA-G and many HLA-A, -B, and -Callotypes. The HCMV protein UL-40 acts as a source of thepeptides that can bind HLA-E. Thus, by supplying a source ofHLA-E-specific peptides, UL-40 stabilizes the expression ofHLA-E on the surface of HCMV-infected cells [105–108].HLA-E inhibits NK cell activation by interacting with theinhibitory receptor CD94/NKG2A. As mentioned earlier,HCMV encodes several proteins to reduce the expression ofMHC class I on the surface of the virus-infected cells. AsHLA-E needs peptides derived from the signal sequences ofother MHC allotypes, the decreased expression of MHC classI would also have decreased the expression of HLA-E on thesurface. By encoding UL-40, HCVM compensates for the lossof peptide pool for HLA-E. More recently, an immunodominantCTL epitope derived from the HIV protein p24 was also shownto bind HLA-E and increase the expression of this MHCantigen on the cell surface [109]. Thus, HIV may also evadeNK cell-mediated lysis by stabilizing and increasing the ex-pression of HLA-E on the surface of the virus-infected cells.

The HCMV also encodes a MHC homologue UL-18, whichforms heterodimers with �2m and can bind endogenous pep-tides. In addition to decreasing the expression of other MHCmolecules by sequestering the �2m, UL-18 interacts with aninhibitory receptor ILT-2 and inhibits NK cell activation [110,111]. It is interesting that ILT-2 is also expressed on macro-phages, B cells, and DC. The virus-encoded protein maytherefore also inhibit activation of these cell types.

When under stress or infected with a virus, the cells expresscertain stress-inducible proteins MIC-A, MIC-B, andULBP1–4. These de novo expressed proteins interact with theNK cell receptor NKG2D and trigger NK cell activity. It isinteresting that the NK cell activation mediated by NKG2D isnot inhibited via inhibitory KIR. Moreover, NKG2D is alsoexpressed on the surface of activated macrophages and certainT cells and is involved in the activation and costimulation ofthese cells. The HCMV-encoded protein UL16 binds to MIC-Band ULBP1 and -2 and decreases their cell surface expression[112–114]. This inhibits killing of the virus-infected cells viaNKG2D. The ULBPs are glycosylphosphatidylinositol-linked

TABLE 3. Viral Strategies to Evade NK Cell Responses

Virus Viral protein Effect on infected cells Effect on NK cells

HIV-1 resistance Nef 2HLA-A, -B but not of HLA-C, -E Maintenance of NKKSHV K5 2HLA-A, -B but not of HLA-C, -E � � �

2ICAM-1, 2B7.2 2NK cell activationEBV EBNA-1 Novel peptides for HLA-A, -B 2NK cell activation via KIR3DLHCMV pp65 2NK cell activation via NKp30

UL40 1HLA-E 2NK cell activation via NKG2AUL18 2NK cell activation via ILT-2

UL141 2CD155 (PVR)2NK cell activation via DNAM-1,CD96 (TACTILE)

UL16 2ULBP1, -2; 2MIC-B 2NK cell activation via NKG2DMCMV m157 Binds LY49I, 2NK cell activation

m155 2H60 2NK cell activation via NKG2Dm152 2H60, Rae-1 � � � � � �m145 2MULT-1 � � � � � �

HCV E2 2NK cell activation via CD81

PVR, Poliovirus receptor; TACTILE, T cell activate increased late expressed; Rae-1, retinoic acid early inducible protein-1; MULT, murine ULBP-liketranscript-1. The arrows 2 and 1 indicate increase and decrease, respectively.


glycoproteins distantly related to the MHC class I family. It isinteresting that these proteins were first identified by theirability to bind to the HCMV protein UL16 [115]. The UL16binds the NKG2D ligands intracellularly and redirects theirintracellular trafficking for lysosomal degradation via a ty-rosine-based sorting signal present in its cytoplasmic tail [115,116].

It has been demonstrated recently that the HCMV UL141gene product blocks the surface expression of CD155, which isknown as a ligand for the activating NK cell receptors DNAM-1(CD226) and TACTILE (CD96) [117]. UL141 is not the onlyHCVM protein that interferes with the interaction of an acti-vating NK cell receptor with its ligand. The most immunodom-inant viral protein pp65 can also bind and inhibit the functionof another activating NK cell receptor NKp30. The proteincauses dissociation of the receptor from the signal-transducingpartner, the � chain [102].

Like HCMV, the MCMV has also developed several strate-gies to evade host’s NK cell responses (Table 3). Its m155 geneproduct can subvert the NK cell cytotoxicity by down-regulat-ing H60, which is a stress-inducible protein that acts as aspecific, high-affinity ligand for NKG2D [118]. The virus en-codes two other proteins m152 and m145, which can interferewith the interaction of NKG2D with its ligands. The m152binds H60 and Rae-1, whereas the m145 can bind and se-quester MULT-1 intracellularly [119, 120]. Like H60, Rae-1and MULT-1 act as ligands for NKG2D for mouse NK cells.These examples clearly show that HCMV and MCVM havedeveloped strategies to inhibit NKG2D-mediated NK cell kill-ing of the virus-infected cells. These strategies may also inhibitmacrophages and prevent costimulation of T cells via thisactivating receptor.

A great deal has been learned about the role of the MCMVprotein m157 in determining susceptibility of the virus-in-fected cells to NK cell-mediated lysis [121–123]. The proteinbinds two NK cell receptors Ly49H and Ly49I. The Ly49H isan activating NK cell receptor, whereas Ly49I is an inhibitoryone. The MCVM-resistant mouse strains express Ly49H, andMCVM-susceptible strains express Ly49I on their NK cells.The interaction of m157 with Ly49-positive NK cells leads totheir activation, proliferation, and release of various cytokinesand chemokines. The passage of the m157-positive MCMV inresistant Ly49-positive mice leads to mutations in m157 pro-tein and escape from the NK cell-mediated control of the viralreplication. Wild-type MCVM also shows mutations in thisviral gene [123]. This is a classical example of a virus under-going mutations under pressure from NK cell-exerted control.

The HCV-encoded major envelope protein E2 interacts withCD81. The latter molecule is a tetraspanin and is expressed asa complex with a variety of receptors on the surface of differentcell types including T, B, and NK cells. The effects of CD81cross-linking with specific antibodies may vary depending onthe cell type. This cross-linking inhibits NK cells. Similarly,the binding of E2 to CD81 inhibits NK cell-mediated cytotox-icity and cytokine release (ref. [124], reviewed in ref. [125]).Furthermore, HCV encodes a serine protease complex, whichis essential for cleaving HCV-encoded polyproteins into bio-logically active proteins. The protease was shown to inhibitactivation (phosphorylation) of IFN regulatory factor-3 (IRF-3),

probably by cleaving and inactivating an upstream kinase[126–128]. The activation is an essential step in the inductionof type I IFN as well as in the IFN-mediated antiviral effects.As stated above, one of the effects of these IFN is to activateNK cells; HCV can evade NK cell activation by preventingIRF-3 activation. Other viruses also use similar strategies toinhibit NK cell activation. For example, the Ebola and Rabiesvirus-encodes P proteins and the respiratory syncytial virus(RSV)-encoded NS1 and NS2 proteins inhibit IRF-3 phosphor-ylation (reviewed in ref. [129]).

The ubiquitous human pathogen EBV has evolved a uniquestrategy to inhibit host’s NK cell responses. The viral proteinEBNA-3A supplies peptides, which can bind certain HLA-Aallotypes [130]. These HLA-peptide complexes are recognizedspecifically by the inhibitory NK cell receptors KIR3DL2. Thisrecognition inhibits NK cells from killing EBV-infected/trans-formed host cells. It is interesting that a variety of peptidesderived from different other human viruses, which bound theseHLA allotypes, was not recognized by these NK cell receptors.It is not yet clear why humans have evolved these KIR recep-tors, which are used by EBV to evade their NK cell-mediatedinnate immunity against this virus.

Moreover, certain viruses encode proteins, which are MHCclass I homologues and can inhibit NK cell activation. TheHCMV encodes MHC class I �-chain homologue UL18, whichcan complex with �2m and bind endogenous peptides. It isresistant to down-regulation by the viral proteins US2, -3, -6,and -11 [41, 131–133]. Similarly, the MCMV encodes a MHCclass I homologue, m144, which confers protection from NKcell effector functions, even when classical MHC class I anti-gens are down-regulated from the surface of the virus-infectedcells. In vivo studies have shown that m144-expressing MHCclass I-deficient lymphoma cells can inhibit activation andaccumulation of NK at the site of immune challenge [134].

Finally, viruses may induce de novo expression of certainMHC antigens and inhibit NK cell functions. For example,HIV induces HLA-G and HLA-E on the surface of HIV-infected cells [109]. Both molecules act as ligands for certaininhibitory NK cell receptors.

Evasion from CTL by antigenic variation

This is an important strategy evolved by RNA viruses, whichhave small genomes and cannot afford to encode many differentimmune-evasion proteins. Because of poor editing functions ofthe virus-encoded polymerases and a high rate of virus repli-cation, several point mutations occur at random in structuraland nonstructural viral protein genes. This leads to the exis-tence of countless closely related, distinct viruses or “quasi-species” in the infected host, where its antiviral immuneresponse exerts a selective pressure on these quasi-species.The virus-specific CTL are unable to recognize the virus-infected cells if the mutations happened to occur in the aminoacid sequence of the epitopes recognized by the CTL. Underpressure from virus-specific CTL, the viruses carrying thesemutations (escape mutants) accumulate in the infected indi-viduals. In a similar manner, viruses may mutate to evadevirus-specific CD4� T cells and virus-neutralizing antibodies.When the infected host develops immune responses to theescape mutants, new escape mutants emerge, which can evade


host’s antiviral immune responses. Furthermore, viruses mayalso undergo antigenic variation by recombination betweendiverse viral strains. By mutating its antigenic determinants,the virus always stays one step ahead of the immune response.This cat and mouse game continues between the virus and thehost’s immune responses until host’s ability to mount an im-mune response is exhausted. All viral epitopes can undergomutations unless the mutation is in a highly conserved regionand compromises a key function of the protein. The mutantviruses may infect another host, and the mutations may persistif the new host does not restrict and present the mutatedepitope. The mutated epitopes, at least in vitro, may act asaltered peptide ligands and anergize or cause apoptosis of thevirus-specific T cell clones. The escape mutants for HIV-1,HCV, and many other viruses have been studied extensively(reviewed in refs. [135, 136]). In the case of HIV-1, it has beendocumented that human populations are selectively accumu-lating viruses with mutated epitopes, which are presented bythe most prevalent HLA allotypes. Nevertheless, the persis-tence of many epitope-encoding HIV sequences has beendocumented in the infected individuals having strong epitope-specific CTL responses, suggesting a complex relationshipbetween immune evasion and antigenic variation Large DNAviruses, which cause chronic infections, such as EBV andHCMV, have also been documented to use this strategy toevade CTL responses [137–139]. The RNA viruses with seg-mented genomes, such as influenza viruses, also undergo an-tigenic variation (antigenic shift) by a reassortment of genomesegments between different viruses. Newly emerged recombi-nant viruses can evade the immunity, which is prevalent in thehost. Such recombinant influenza viruses have caused greathavoc in the human history. The influenza virus that caused the1918 pandemic resulted from such reassortment events occur-ring between human and nonhuman influenza viruses [140].The antigenic variability of viruses is a great hurdle in devel-oping effective antiviral vaccines.

Immune evasion through latency

The state of a reversible, nonproductive viral infection in thehost cells is called latency. Viruses may evade immune re-sponses of the host by becoming “latent” and invisible to theimmune system. During latency, viruses may infect nonpermis-sive or semipermissive cells of the host and express only aminimum number of viral genes, which are just necessary tomaintain the virus in the cells. The ubiquitous human pathogenEBV represents a classic example of viral latency [141]. Thevirus only expresses one protein EBNA-1 and two nonpoly-adenylated, short RNA molecules (EBV-encoded small RNAor EBER-1 and -2) in certain latently infected host cells. Thevirus becomes active and replicates only when the cell be-comes activated. The newly produced virions then infect an-other lot of host cells. Some viruses may persist in immune-privileged tissues of the host, e.g., brain, retina, and kidney.For example, HSV-1 infects and replicates in epithelial cellsbut persists as latent infection with little gene expression insensory neurons of Trigeminal ganglia, which do not expressMHC antigens [142]. The virus expresses only one gene, thelatency-associated transcript gene, which inhibits viral repli-cation. Upon proper stimuli, such as immunosuppression,

trauma, or exposure to sun or ultraviolet radiation, the virusmay activate itself and descend down axons of the neurons andinfect epithelial cells. Similarly, Herpes zoster virus becomeslatent in dorsal root ganglions of the spinal cord. Anotherherpesvirus, HCMV, persists for long periods of time in kidney,retina, and bone marrow. HIV-1 is known to persist as a latenttranscriptionally inactive provirus in the host cell’s genome inlong-lived, resting CD4� memory T cells [143]. These cellsmay lack virus-needed transcription factors. The virus mayalso persist in the brain, which is protected by blood brainbarrier from infiltration of lymphocytes. These cells and tissuesserve as reservoirs of the virus, which are resistant to chemo-therapy and represent a real challenge for a complete elimi-nation of the virus from the infected host.

Targeting immune cells

Many viruses have developed the strategy of infecting immunecells, which play a key role in orchestrating antiviral immuneresponses. For example, HIV-1 infects CD4� T cells. Thedepletion of these cells is a hallmark of HIV-induced AIDS. Ithas been shown that HIV-specific CD4� T cells are moresusceptible to HIV infection than HCMV-specific CD4� Tcells, as the former cells preferentially migrate to the sites ofHIV infection [144]. CD4� T cells play an important role inthe generation of virus-specific CTL and antibodies. The lackof help from CD4� T cells is probably one of the reasons forincomplete differentiation of HIV-specific CTL in HIV-in-fected individuals [145, 146]. Consequently, these CTL arecompromised in their cytotoxic abilities and are unable to clearthe infection [147]. Many viruses, e.g., the reovirus and mea-sles virus, infect DC and induce the expression of TRAIL andFasL on their surface [148]. Such DC cannot present antigensand prime T cells for the generation of virus-specific CTL.Instead, they kill interacting T, B, and NK cells via Fas/FasLand TRAIL/DR interactions (Fig. 1). The virus-infected DCmay in fact induce immunosuppression instead of an antiviralimmune response. The human pathogen HSV-1 infects andinduces apoptosis in immature DC by decreasing the expres-sion of cellular Fas-associated death domain-like IL-1�-con-verting enzyme (FLICE)-inhibitory proteins (cFLIP) at themRNA level. The virus also increases the expression of TNF-�and TRAIL in these cells. These ligands induce apoptosis inthe virus-infected DC [149]. The HIV protein Nef was shown tobind CXC chemokine receptor 4 and induce apoptosis ofCD4� T cells [150]. Another HIV protein Vpr inhibits DCmaturation and impairs their ability to activate virus-specificCTL and memory T cell [151].

Interference with apoptosis of the virus-infectedhost cells

Apoptosis or programmed cell death is a physiological process,whereby the cell causes its own death through a regulated andcontrolled process of degradation of its protein and DNAcontents by its own enzymes [152]. It is a relatively silent andnoninflammatory process. The cells may undergo apoptosisthrough an extrinsic or intrinsic pathway. The extrinsic path-way is activated when external factors such as TNF-�, FasL, orTRAIL bind to their specific receptors, so-called death recep-


tors or DR, a family of TNFR-related proteins expressed on thecell surface. The oligomerized DR recruit the adapter Fas-associated death domain (FADD) via their death domains (DD).The death effector domain (DED) of FADD interacts with theDED of procaspase 8 or 10 (also called FLICE). This results inthe proteolytic cleavage and activation of these caspases. Theintrinsic pathway is activated upon the release of cytochrome c,direct inhibitors of apoptosis proteases (IAP)-binding protein(DIABLO), and other proapoptotic factors from mitochondria.The cytochrome c forms a complex, the death-inducing signal-ing complex (DISC), with apoptosis protease-activating factor-1and procaspase-9, resulting in the activation of the latter.DIABLO binds and inhibits cellular IAP and allows activatedcaspases to mediate their effects. Cells may undergo apoptosisthrough this pathway when subjected to irreparable DNA dam-age, viral infections, or physical and chemical insults. There isan active cross-talk between the two pathways. The activationof one may lead to activation of the other pathway. A criticalstep in this cross-talk is the cleavage of the proapoptoticprotein Bid by caspase-8, which is activated by the extrinsicpathway. The cleaved Bid promotes cytochrome c release andactivation of the intrinsic pathway of apoptosis. Both pathwayslead to a series of caspase and DNase activation events,causing a controlled degradation of cellular proteins and DNA.It is noteworthy that NK and CTL use apoptosis as the principalmechanism for killing virus-infected cells. They do so byreleasing certain cytotoxic molecules, such as TNF-�, perforin,and granzymes, as well as by engaging DR on the surface of thevirus-infected cells. It is noteworthy that the granzyme B,which is released by CTL and NK cells and is endocytosed bythe target cells, can activate several caspases directly.

Viruses encode various proteins to modulate apoptosis totheir own advantage (Table 4). They inhibit premature apo-ptosis of the virus-infected cells (before replication of the virushas occurred). After completion of the viral replication, virusesmay promote apoptosis to disseminate progeny virus withoutcausing inflammatory responses. Viral antiapoptotic strategiesalso help the virus evade CTL and NK cell-mediated killing ofthe virus-infected cells.

The host cells respond to many viral infections by inducingand activating the proapoptotic antioncoprotein p53. It is oneof the main sensors of the cell for activating the intrinsicpathway of apoptosis. Furthermore, it also activates transcrip-tion of many proapoptotic genes, e.g., Bax, Fas, and TRAIL-receptor-2, and represses transcription of the antiapoptoticgene Bcl-2. Upon its activation, the virus-infected cell coulddie before the virus has completed its replication. To evade thispremature apoptosis of the infected cells, many viruses encodeproteins that bind and inactivate p53 by a variety of mecha-nisms. The examples include SV-40 large T antigen, adenovi-rus E1B (55K), human papillomavirus E6, and the pX proteinof Hepatitis B virus [153]. The human T-lymphotropic virusprotein Tax and the EBV oncoprotein latent membrane protein1 repress transcriptional activity of p53 [154, 155]. The mu-tated adenoviruses, which lack the ability to encode p53-binding viral proteins, replicate and kill p53 mutant humancancer cells efficiently. These observations have led to thedevelopment of a new class of therapeutic oncolytic viruses fortreating a variety of cancers [156]. Oncogenic viruses also useanother strategy to block apoptosis by the intrinsic pathway.They encode Bcl-2 homologues, which prevent the release ofcytochrome c from mitochondria. The examples include E1B-19K of adenoviruses, the BHRF1 and bronchoalveolar lavagefluid-1-encoded proteins of EBV, and KSbcl-2 of KSHV (re-viewed in ref. [153]). The HCMV gene US37 encodes a protein,the viral mitochondria-localized inhibitor of apoptosis, whichhas no sequence homology to Bcl-2 but localizes in mitochon-drial membranes like bcl-2 and inhibits Fas-mediated apopto-sis [157]. The HSV encodes a protein kinase US3, whichphosphorylates Bad and prevents Bad-induced activation/am-plification of apoptosis [158].

Many viruses can escape the apoptosis mediated via theextrinsic pathway by encoding viral FLIP (vFLIP), which mim-ick FLICE, contain DED, and associate themselves with DRbut lack the caspase activity [153, 159]. The mechanism ofaction of vFLIP is shown in Figure 4. Many �-herpesviruses,including the HHV8, herpesvirus saimiri, equine herpesvirus2, bovine herpesvirus 4, and moluscum contagiosum virus,encode vFLIP [160, 161], which disrupt recruitment of pro-caspase-8 to the DISC. Two forms (short and long) of thecellular ortholog of the vFLIP have also been identified (seebelow). They compete with the adaptor FLICE and regulateapoptosis [162]. The HCMV UL36 gene product, the vICA,also associates with procaspase 8 and blocks its activation (Fig.4), but none has sequence identity with other vFLIP, suggest-ing that this viral protein represents a new class of cell-deathsuppressors [163]. The vFLIP can also inhibit apoptosis byincreasing the expression of nuclear factor (NF)-�B throughtheir interactions with different adaptor proteins, includingTNFR-associated factor-2, NF-�B-inducing kinase, and inhib-itor of I�B kinase-2 [164]. The cellular ortholog of vFLIP hasbeen cloned, and it generates two protein forms as a result ofalternate splicing: a short, 26 kD, and a long, 55 kD, form.Both forms can delay or inhibit apoptosis by recruitment to theDISC [159].

Caspases are cytosolic proteins with a cysteine-based, as-partate-directed protease activity. They are involved in thetransduction of the apoptotic signals inside the cell as well as

TABLE 4. Viral Strategies to Evade Apoptosis

1. Directly inhibiting the enzymatic activities of the caspases byencoding viral IAP, e.g., Baculovirus p35, poxvirus CrmA.

2. Encoding FLIP homologues and inhibiting the recruitment ofFLICE into DISC, e.g., KSHV K13, HVS orf 71.

3. Down-regulating death receptors on the surface of virus-infectedcells, e.g., adenovirus RID complex.

4. Increasing DR ligands FasL and TRAIL on the surface of virus-infected cells, e.g., measles virus unknown protein, HIV Nef.

5. Encoding homologues of the antiapoptotic Bcl-2 family proteins,e.g., BHRF-1 of EBV.

6. Inactivating proapoptotic Bcl-2 family members, e.g., HIV Nefpromotes Bad phosphorylation.

7. Inhibiting p53 activation, e.g., SV40 large T antigen, adenovirusE1B.

8. Interfering with intracellular signaling molecule, e.g., Nefinhibits ASK-1.

CrmA, Cytokine response modifier-A; orf 71, open reading frame 71; SV40,simian virus 40; ASK-1, apoptosis signal-regulating kinase-1.


in the execution of most of the physical manifestations of theapoptosis. Many viruses encode proteins, viral IAP (vIAP),which inhibit the enzymatic activity of caspases [165, 166]. Forexample, the baculovirus p35 gene product inhibits Fas andTNF-induced apoptosis by inhibiting caspases [167]. The HSVgene, US5-encoded glycoprotein gJ, has been shown to inhibitFas and granzyme B-mediated apoptosis by blocking activationof caspase-3 [168]. All poxvirus genomes encode vIAP toinhibit apoptosis. The cowpox virus protein, the CrmA, caninhibit several caspases, probably via covalent modification ofcaspase 8, and prevents or delays apoptosis mediated by CTL,NK cells, TNF-�, and FasL [169–173]. Eight cellular coun-terparts of vIAP have been identified. They can inhibit theeffector (caspase-3, -6, and -7) and initiator caspases(caspase-9) and modulate apoptosis in cells (reviewed in refs.[152, 153]).

The HIV protein Nef protects the virus-infected cells fromapoptosis by interfering with an essential signaling molecule,the ASK1, which is a serine/threonine kinase involved in theformation of a key signaling intermediate in the FasL- andTNF-�-induced death pathway [174]. This protects HIV-in-fected cells from apoptosis as a result of the cis ligation of Fasby FasL, as the virus increases the expression of Fas and FasLon the surface of the infected cells.

Some viruses can evade host’s cellular immune response byregulating the expression of DR ligands to their own advantage.

The measles virus induces the expression of TRAIL in infectedhuman monocyte-derived DC (Fig. 1). These DC become cy-totoxic and induce immunosuppression by killing interacting Tcells instead of priming and activating them [148]. The HCMV-infected DC also express TRAIL and FasL and delete T cells[175, 176]. Moreover, HSV-1 infects activated human CTL andincreases their susceptibility to apoptosis by FasL. Conse-quently, the antiviral CTL kill each other by fratricide [177].These strategies enable the infecting virus not only to counterand evade host’s antiviral immune response but also to induceimmunosuppression in the infected host.

Adenoviruses protect virus-infected cells from apoptosis byinhibiting the expression of DR on the cell surface. The E3region of all adenoviruses encodes three integral membraneviral proteins: E3-10.4K, E3-14.5K, and E3-6.7K. They areexpressed as heteromeric complexes, receptor internalizationand degradation (RID) complexes, which reduce the membraneexpression of Fas and receptors for TRAIL and epithelialgrowth factor [178–181]. The loss of these receptors leads toprotection of the virus-infected cells from the cytototoxic ac-tivity exerted by CTL and NK cells [182]. The RID complexes,however, do not target the transferrin receptor or MHC class Iantigens [179]. The complexes redirect intracellular traffickingof the DR to late endosomes for degradation. The SIV proteinNef increases the expression of FasL on the surface of thevirus-infected cells, which can evade antiviral CTL by causing

Fig. 4. vFLIP compete with the recruitment of FLICE to the DISC. The vFLIP are homologues of cFLIP. They interact with the DD of the DR, e.g., Fas, TNFR.However, they lack DED and cannot recruit FLICE (procaspse 8). Without FLICE, no DISC is formed, and caspases are not activated to affect apoptosis. The HCMVviral inhibitor of caspase 8-induced apoptosis (vICA) binds directly and inhibits caspase 8. TRADD, TNFR1-associated signal transducer


their apoptosis via Fas/FasL interactions [183]. This mecha-nism has also been used by HIV protein Nef, which increasesthe expression of FasL and TNF-� in DC. Exogenous Nef alsotriggers apoptosis of CD8� T cells by activating caspase-8.Collectively, these effects abrogate the ability of DC to primeand activate alloreactive CD8� T cells. The cells rather be-come anergic and show decreased proliferation, cytoxocity, andIFN-� production [184]. The viral protein Tat induces expres-sion of TRAIL in primary human macrophages [185]. HIV alsodirectly promotes apoptosis of immune cells to evade host’santiviral immune responses [186]. The Tat protein acts as aproapoptotic protein by up-regulating the sensitivity of CD4�T cells to Fas-mediated apoptosis, mainly by increasing theactivity and expression of caspase-8 [187, 188]. Another HIVprotein Vpu also enhances the susceptibility of CD4� T cellsto the Fas-induced apoptosis [189]. By these mechanisms,HIV-1 manipulates the apoptotic machinery to its advantage ininfected and uninfected cells. It promotes unresponsivenessand death of neighboring, uninfected immune cells but protectsthe virus-infected cells from apoptosis.

Targeting cytokines and chemokines of the host

The cytokines and chemokines are host cell-secreted polypep-tides, which bind to their specific cell surface-expressed re-ceptors and modulate activation, proliferation, and migration ofvarious cell types involved in the induction of immune re-sponse and inflammation in vial infections. By communicatingbetween different cells, they coordinate and orchestrate differ-ent components of the innate and adaptive immune responses(reviewed in ref. [190]). The host responds to viral infections bystimulating production of a variety of cytokines and chemo-kines. It is not surprising that viruses have developed severalstrategies to counter these responses. These strategies includeencoding inhibitors, decoy receptors, or modified viral versionsof these soluble mediators (summarized in Table 5; ref. [191]).

The poxviruses and herpesviruses modulate host’s cytokineresponses by producing proteins, which act as mimics forcytokines or their receptors. The BCRF-1 open-reading frame(ORF) of EBV encodes a protein (vIL-10), which is a homo-logue of the human IL-10 [192]. The HCMV UL111a gene alsoencodes an IL-10 homologue, which shares 27% sequencehomology with human IL-10 [193]. Both the vIL-10s are highlyimmunosuppressive and can inhibit production of IFN-� andTNF-� from monocytes. They also inhibit the mitogen-stimu-

lated proliferation of peripheral blood mononuclear cells(PBMC) and decrease expression of MHC class I and class IIantigens and costimulatory molecules ICAM-1, CD80, andCD86 but increase the expression of HLA-G on human PBMC[194, 195]. The two viruses seem to have usurped the humanIL-10 gene by different mechanisms [195]. They have modifiedthe gene, retaining its immunosuppressive and anti-inflamma-tory properties, but not the immunostimulatory ones. The en-coding of an IL-10 homologue is not restricted to herpesvi-ruses; a poxvirus-encoded protein Y134R was also recentlyshown to have IL-10-like activities [196].

Concerning chemokines, the herpesviruses such as KSHV,HHV6, and HCMV encode proteins, which bear sequencehomology to human chemokines MIP-1 [191]. Certain virus-encoded chemokines may evade immune responses by actingas antagonists (e.g., vMIP-2 of KSHV), and others may facili-tate virus spread by acting as agonists (e.g., U83 protein ofHHV6). Furthermore, certain virus-encoded chemokine-likeproteins may skew the immune response by chemoattractingTH-2 type CD4� T cells (e.g., vMIP-1, -2, and -3 of KSHV).Some viruses may encode proteins, which have no sequencehomology to any known chemokine but still may have chemoat-tractant properties. The HIV Tat and the RSV protein G aresuch proteins. The RSV uses protein G to gain entry in cells viathe fractalkine receptor [197].

The poxviruses and herpesviruses encode proteins, whichare similar in sequence to the extracellular ligand-bindingdomains of certain cytokine or chemokine receptors but lacktheir intracytoplasmic tails. Functionally, they act as decoyreceptors and neutralize the bound cytokines and chemokinesof the host, as they can bind the cytokine or the chemokine butcannot transmit signals. A good example is the cowpox, whichencodes at least four different TNFR [191, 198]. Similarly,viruses have targeted other cytokine receptors (e.g., includingIL-1�R, IFN-�R, CD30). Viruses also modulate the chemo-kine system of the host by encoding certain chemokine recep-tor homologues. The examples include the ORF74, US28, andUS27 proteins of KSHV, HCMV, and HHV6, respectively. Thevirus-encoded chemokine receptors are expressed on the sur-face of the infected cells, and their role in immune evasion isnot yet fully understood (reviewed in ref. [191]).

In addition to encoding decoy receptors, viruses also encodehomologues of the cellular proteins that can bind and inhibit acytokine. The certain poxviruses such as cowpox virus, ec-tromelia virus, and vaccinia virus encode a soluble proteinvIL-18BP, which like its cellular homologue, binds and neu-tralizes the biological activity of IL-18 [199]. It is noteworthythat in concert with IL-12, IL-18 strongly stimulates antiviralcellular immunity. Similarly, vaccinia virus encodes a vIFN-�/�BP, which binds to the cell surface after secretion andprevents IFN from binding to its receptors. Similar to thevirus-encoded cytokine-binding proteins, viruses also encodeproteins that can bind chemokines and neutralize them. Themyxoma virus encodes M-T7 [or virus chemokine-binding pro-tein 1 (vCKBP-1)], which can bind and inactivate severalchemokines. However, the poxvirus-encoded chemokines donot bind to M-T7. The vCKBP-2 binds to C–C chemokines andis encoded by myxoma and vaccinia viruses. The thirdvCKBP-3 (also called M-3) is encoded by the MHV-68 and

TABLE 5. Viral Strategies to Target Host’sCytokines and Chemokines

Viruses evade host’s cytokine and chemokine responses byencoding:

1. Viral versions of cytokines, e.g., HCMV and EBV vIL-10.2. Viral versions of chemokines, e.g., KSHV K6 (vMIP-1).3. Cytokine receptor homologues, e.g., Cowpox virus TNF-R.4. Chemokine receptor homologues, e.g., KSHV Orf 74, HCMV

US28.5. Cytokine-binding proteins, e.g., vaccinia virus IL-18BP.6. Chemokine-binding proteins, e.g., myxoma virus MT-7.7. Viral proteins with chemokine-like activity, e.g., HIV Tat.

IL-18BP, IL-18 binding protein.


inactivates almost all chemokines. Expectedly, the M-3 mutantMHV was found to be less pathogenic in mice [200].

The cowpox virus CrmA inhibits caspase-1, also calledIL-1-converting enzyme, which is needed to cleave precursor,immature IL-1� and IL-18 into biologically active, maturecytokines [201].

Mimicking Fc�R

Viruses may also use other strategies to evade host’s cellularimmune responses. The MCMV, HCMV, and HSV-1 encode atleast one protein, which mimics a Fc�R [202, 203]. The Fc�Rhomologues are thought to prevent macrophage activation fromimmune complexes and protect virus-infected cells from NKcell killing via ADCC. They also inhibit clearance of antibody-coated pathogens from the circulation.

Deregulating immune responses viasuperantigens (SA)

SA are molecular structures, which bind MHC class II to a sitedistinct from the antigen-binding groove on APC and to par-ticular variable regions of the �-chain of the TCR. Each SAbinds to a specific subset of V� elements. SA are powerful Tcell mitogens and induce uncontrolled activation of their cog-nate V�-bearing T cells. A good deal has been learned aboutbacterial SA, more than 40 of which have been identified(reviewed in ref. [204]). A SA-encoding human endogenousretrovirus (HERV)-K18 has been identified in humans. Theprovirus is located on human chromosome 1 in the first intronof CD48 in reverse orientation and has three alleles. Thetruncated envelope protein of the virus acts as a SA, which canbind V�-7- and V�13-containing TCR (ref. [205]). Severalstudies suggest that viruses, such as EBV, HIV, HCMV, andrabies virus, encode SA. These conclusions were drawn, as theindividuals suffering from these viral infections exhibited un-usual expansions of certain V�-bearing T cell subsets (re-viewed in ref. [206]). However, the exact identification of theSA encoded by these viruses has remained elusive. It isinteresting that Sutkowski et al. [207] have demonstrated thatEBV does not encode any SA per se; it rather activates theSA-encoding HERV-K18 at the transcriptional level. Theseresults explain the expansion of V�13-positive T cell subsetsin EBV-infected individuals. Apart from EBV, IFN-� has alsobeen demonstrated to activate this endogenous retrovirus inhuman PBMC (ref. [208]). It is quite possible that the SA-likeactivities observed in other human viral infections might alsobe a result of their activation of some unknown SA-encodingendogenous retroviruses. By encoding and/or inducing theexpression of SA, the viruses may evade host’s antiviral cellu-lar immunity via activating, nonspecific T cells and thus shift-ing the focus of the immune response away from the virus. Theymay also use the T cell-secreted cytokines and growth factorsto propagate their own target cells. For example, the mousemammary tumor virus-encoded SA induces T cell activation,which is essential for propagation and infection of target B cells(ref. [209]). Similarly, EBV may also require T cell help toinfect B cells. Because of their ability to activate a largenumber of T cells with diverse antigenic specificities, SA maypredispose the host to autoimmunity by inadvertently activat-

ing T cells with cross-reactivity to self-antigens. In fact,HERV-K18 has been implicated in the pathogenesis of insu-lin-dependent diabetes mellitus in humans (ref. [205]).

CONCLUSIONS

Viruses have evolved a diverse array of strategies to evadehost’s immune responses. These strategies are as diverse as theviruses themselves. In general, each virus uses multiple strat-egies for immune evasion. Large DNA viruses can afford toencode multiple proteins that target different aspects of theimmune response. Small RNA viruses mainly rely on antigenicvariability as the principal immune evasion mechanism. Thedown-regulation of MHC antigens on the surface of virus-infected cells is a strategy used by many diverse viruses,suggesting the importance of virus-specific CTL in controllingthe replication of these viruses in the infected host. However,as exemplified by HIV-1, HCV, HCMV, and MCMV, theviruses also have to develop mechanisms to avoid being killedby NK cells. In fact, we are only beginning to understand theimmunobiology of these cells. As many viruses differentiallydown-regulate HLA (-A and -B but not -C) molecules tosimultaneously evade killing of the virus-infected cells by CTLand NK cells, the viral epitopes presented by HLA-C may beused for vaccine purposes. Efforts should be directed at devel-oping reagents, which could block the action of the viralproteins involved in the degradation of the host MHC antigens.The viral proteins, which increase resistance of the virus-infected cells to NK and CTL-mediated killing, may representideal molecular targets for developing novel antiviral drugs.Understanding viral immune evasion mechanisms allows us abetter understanding of the host parasite interactions and theircoevolution. This knowledge may also enable us to deviserational strategies for countering these evasion mechanisms.

ACKNOWLEDGMENTS

A. A. is the recipient of a “Chercheur-boursier senior” awardfrom the “Fonds de la recherche en Sante du Quebec.” O. D.holds a scholarship from the Ste-Justine Hospital Foundation,Montreal. We thank all our colleagues for helpful discussionson the subject and the Canadian Institutes of Health Researchfor support. We regret that due to space limitations, all studieson the subject could not be cited.

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