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Viral strategies for evading antiviral cellular immune responses

of 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 molecular 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 themselves

with an elaborate immune system to defend themselves from

the invading viruses and other pathogens. The viruses, on their

part, have developed many strategies to evade host’s antiviral

immune responses. These strategies, which have allowed vi-

ruses to replicate and persist successfully in the host, will be

discussed in this article. We will begin this discussion with a

brief overview of the antiviral immune responses of the host.

ANTIVIRAL IMMUNE RESPONSESOF THE HOST

The immune system can be defined as an overall coordination

of the biological mechanisms involved in the integrity and

protection of the host from malignancy and infectious agents

such as viruses. The system can be divided arbitrarily into two

major parts: the innate and adaptive. The principal immune

effector 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, or

double-stranded viral RNA, via a variety of so-called pattern

recognition receptors, which include Toll-like receptors, NK

cell receptors, and mannose-binding receptors [1, 2]. These

cells then release a variety of proinflammatory cytokines and

chemokines, which recruit inflammatory cells to the site of

infection 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 lymph

nodes to present antigen to T and B cells. Viral infections are

usually accompanied by NK cell activation. Activated NK cells

kill virus-infected cells and serve as an immediate source of

interferon- (IFN-). The killing of virus-infected cells is an

important danger signal to initiate immune response. The NK

cell-secreted IFN- plays an important role in inducing an

effective antiviral immune response. An important event is the

induction of type I ( and ) IFN. Although almost all cell

types can produce these IFN, a specialized cell type, precursor

plasmacytoid DC, produces 1000-fold more of these cytokines

and is called the natural IFN-producing cell [3, 4]. IFNs also

increase expression of major histocompatibility complex

(MHC) class I and II antigens and of costimulatory molecules

on the surface of so-called antigen-presenting cells (APC). The

professional APC include DC, macrophages, and B cells. They

present virus-derived antigenic peptides to naı ¨ve CD8 T

cells and CD4 T cells in association with MHC class I and

class 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 innate

immune system plays an instructive role (adjuvant effect) for

the induction of virus-specific, adaptive immune responses. In

general, exogenous viral particles and viral antigens are phago-cytosed and/or endocytosed by APC. They are then degraded in

lysosomes, and immunogenic peptides are presented in asso-

ciation with MHC class II antigens to naı ¨ve 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-1

and TH-2 [6]. The two types of the Th cells differ in the

expression of their cytokine profiles. The TH-1 and TH-2 cells

produce and differentiate in response to IFN- and interleukin

(IL)-4, respectively. The role of IFN- in the differentiation of

TH-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 the

production of immunoglobulin G2a (IgG2a) in mice and IgG1

and IgG3 in humans and activate macrophages and CD8CTL. These responses are essential for clearing intracellular

pathogens. The TH-2 cells produce IL-4, IL-5, IL-9, and IL-13

and promote the production of IgG1 and IgE in mice and IgG4

and IgE in humans. They inhibit macrophage activation and

promote 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 responses

is believed important for inducing effective antiviral immune

responses 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 present

antigenic peptides derived from the endogenously expressed

viral proteins in association with classical MHC class I mole-

cules to naı ¨ve CD8 T cells. These CD8 T cells expand and

differentiate into virus-specific effector CTL. The virus-specific

CD4 Th cells also play an important role in the generation of

CTL 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 kill

them 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/DR

interactions may also play a role in this killing. The generation

of virus-specific memory T cells is important for an efficient

virus-specific anamnestic response, a criterion desired for an-

tiviral vaccines.

NK cells and macrophages also kill virus-infected cells in

association with virus-specific antibodies. NK cells kill anti-

body-coated, virus-infected cells via antibody-dependent, cell-

mediated cytotoxicity (ADCC). Virus-specific ADCC plays a

significant role in killing virus-infected cells, especially

against 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 and

from 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 necrosis

factor (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 loading

compartments.

Iannello et al. Viral immune evasion strategies 17



ruses [9]. Macrophages and polymorphonuclear leukocytes can

engulf antibody-coated pathogens as well as virus-infected

cells and/or kill them via reactive oxygen species, nitric oxide,

and activated caspases.

NK cells may also kill virus-infected cells without help from

antibodies [10]. These cells, however, usually do not recognize

any viral antigen or viral peptide per se. Their effector function

is controlled by a complex system of inhibitory and activating

NK cell receptors and coreceptors. They kill target cells unless

inhibited by the engagement of inhibitory receptors by their

cognate 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 to

classical and nonclassical MHC class I antigens; also called

human leukocyte antigen (HLA)-A, -B, -C, -E, and -G ( Table

1). It is noteworthy that most of the KIR recognize HLA-C and

inhibit NK cells. A down-regulation of the MHC antigens on

the 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 cells

and CTL represent the most important cytolytic cells leading to

the 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 adaptive

antiviral immune mechanisms is to seek out and destroy vi-

ruses and virus-infected host cells. Viruses have developed

various strategies to subvert host’s antiviral responses to ensure

their own replication and survival. In recent years, a lot of new

information has become available about the biology of many

different viruses, which required an update on existing reviews

on 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 A

2. 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 ? I

D. 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 (FcRIIa) 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; FcRIIa, 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.

18 Journal of Leukocyte Biology Volume 79, January 2006 http://www.jleukbio.org



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

responses

As APC present virus-derived antigenic peptides in association

with MHC class I antigens to prime antiviral CTL, viruses

interfere with this antiviral response by down-regulating the

expression of MHC class I molecule on the surface of APC. The

virus-specific CTL recognize virus-derived antigenic peptides

in association with MHC class I antigens. A decreased expres-

sion of these antigens on the surface of the virus-infected cells

prevents their recognition and killing by the CTL. As shown in

Figure 2 and summarized in Table 2, viruses use many

different strategies for this purpose. They may do so by the

following:

Repressing transcription of MHC genes

The Tat protein encoded by HIV-1 is a transcriptional activator

of the viral long terminal repeat. However, it can also repress

several 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 with

the transcription factor IID complex and inhibit the histone

acetyl transferase activity of the TFII250 factor, causing re-

pression of several genes involved in the induction of immune

response, e.g., MHC class I and 2m [18–20]. The E5 and E7

proteins of the bovine and human papillomaviruses are onco-

proteins, which are expressed early in the viral life cycle in the

Golgi complex (GC) and ER. They reduce MHC class I mRNA

levels with a certain degree of specificity as well as retain MHCantigens in the GC and ER [21, 22]. The E1A early protein of

the oncogenic adenovirus Ad12 also inhibits transcription of

all components of the MHC class I pathway.

Fig. 2. Interference of viral proteins with antigen

presentation via MHC class I. The endogenous pro-

teins are degraded by 26S proteasome, and the

peptides are actively transported into ER for load-

ing onto nascent MHC heavy chains, which are

associated 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 antigens

then exit ER to the cell surface via the Golgi net-

work. The viral proteins and the steps, at which they

interfere with this antigen presentation pathway, are

shown in red. EBNA-1, Epstein-Barr virus (EBV)

nuclear antigen-1; HSV-1, Herpes simplex virus

type 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 II1. Decreasing the transcription of MHC class I genes, e.g., HIV

Tat, 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 surface

requires the availability of peptides in the ER. The peptides

are produced in the cytosol via proteasomal degradation of viral

proteins (Fig. 2). Many viruses have developed the strategy of

inhibiting this degradation and limiting the pool of available

peptides. For example, the EBV encodes a nuclear protein,

EBNA-1, which is essential for replication of the viral episome

in dividing virus-infected/transformed cells. The protein con-

tains a glycine-alanine-rich (GAr) domain, which inhibits its

degradation by the 26S proteasome, thus reducing the pool of

EBNA-1-derived peptides that could be presented with MHC

class I antigens on the cell surface [23]. Furthermore, the GAr

motif also inhibits translation of the EBNA-1 mRNA in cis, and

this effect can be distinguished from its effect on proteasomal

degradation. By limiting its production at the translational

level, EBNA-1 effectively decreases synthesis of defective

ribosomal 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-1

needed for its replication without antigenic presentation by the

MHC class I, which could lead to the generation of CTL againstthis viral protein as well as recognition of the infected cells by

virus-specific effector CTL [23].

Blocking TAP functions

Many viruses can inhibit the loading of antigenic peptides onto

MHC 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 MHC

class I molecules. As stated earlier, without peptides, MHC

class I molecules cannot fold properly and be expressed on the

cell 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 and

edits 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 is

a thiol oxido-reductase, which isomerizes intrachain S–S

bonds. Many viruses encode proteins that can interfere with

TAP functions and hence, with the translocation of peptides

into the ER. The bovine herpesvirus-1-encoded protein

UL49.5 is a potent inhibitor of TAP. It inhibits TAP by

inducing a conformational arrest of the transporter as well as by

targeting 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-1

protein 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 I

antigens [26, 27]. The ICP47 binds to the cytosolic side of TAP

and blocks its function, whereas E3-19K binds TAP and MHC

and acts as a competitive inhibitor of tapasin. The HCMV-

encoded protein US6 can transiently associate itself with the

TAP 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 also

been demonstrated that the US6 binds to the luminal side of

TAP and allosterically inhibits its ATPase activity [33, 34].

The disruption of TAP function, however, does not affect

expression 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 MHC

class I by degrading the PLC. The HCMV unique short region

genes encode at least four proteins US2, US3, US6, and US11.

Each of them can independently down-regulate the expression

of MHC class I antigens on the surface of the virus-infected

cells. The US2 and US11 induce a rapid degradation of the

nascent HLA class I molecules during their synthesis [36, 37].

The US2 binds to the MHC class I molecules during their

glycosylation, 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-encoded

MHC 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 homologue

may also sequester 2m and inhibit MHC class I expression on

the cell surface. Crystallographic studies have shown that US2

associates with HLA-A2 at the junction of the peptide-binding

region and the 3 domain, a binding surface that allows US2 to

bind the MHC molecule independently of the peptide sequence

and to exert its down-regulatory effects [43].

Poxviruses and -herpesviruses share the K3 family of viral

immune evasion proteins (immunoevasins), which possess anamino-terminal plant homeodomain/leukemia-associated pro-

tein domain or more specifically, a really interesting new gene

with conserved cysteins and histidine residues (RING-CH)

domain, followed by two transmembrane domains. The K3

family proteins have ubiquitin (Ub) ligase activity [44, 45].

They inhibit the surface expression of glycoproteins, such as

MHC 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 viral

immune evasion proteins have been derived from the cellular

MARCH proteins. The MARCH proteins regulate endocytosisof cell surface receptors via ubiquitinylation [46]. The KSHV

proteins K3 and K5 [also called modulator of immune recog-

nition (MIR)-1 and -2, respectively] as well as the MHV-68

protein MK3 prevent the surface expression of MHC class I

molecules [47–49]. MIR-1 and MIR-2 also down-regulate the

surface expression of CD-1 [50], a family of antigen-presenting

molecules, which are distantly related to MHC class I molecules

and present lipid and glycolipid antigens to T and NK-T cells. The

protein MK3 resides in the ER membrane, where it binds to and

ubiquitinylates the cytoplasmic tails of newly synthesized MHC

class I heavy chains while bound to peptides in the PLC,




leading to their proteasome-dependent degradation [51]. It can

also degrade Tapasin and TAP in a RING finger-dependent

manner [52]. Studies about a model for the interaction of MK3

with MHC-I and the PLC have shown that MK3 interacts with

TAP-1 and -2 via their C-terminal domains and with class I

molecules via their N-terminal domains [53]. It is interesting

that the K5-mediated down-regulation of MHC class I mole-

cules does not render the virus-infected cells susceptible to NK

cell-mediated lysis, as it also down-regulates the expression of

ICAM-1 and B7.2 on the infected cells. These molecules act as

ligands for NK cell-mediated cytotoxicity. De novo expression

of B7.2 and ICAM-1 in the K5-expressing cells restores their

sensitivity to NK cells [54]. Furthermore, unlike K3, which

down-regulates all MHC allotypes, K5 only degrades HLA-A

and -B but not HLA-E, and the effect on HLA-C is weak [54].

The myxoma virus (a poxvirus) ER resident protein M153R

down-regulates MHC class I and has been shown to have

Ub-ligase activity in vitro [55].

Viruses have evolved strategies to affect intracellular traf-

ficking of MHC class I antigens and cause its retention inside

the ER. The HCMV US3 protein associates itself with the MHC

class I heavy chain/2m complex and causes its retention in

the 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, and

m4, which are involved in the interference with MHC-I expres-

sion and/or recognition. The m152 blocks the export of MHC-I

from a pre-Golgi apparatus, whereas m6 directs it to lysosomal

degradation (Fig. 2). The MCMV m4 encodes a glycoprotein,

gp34, which is expressed on the cell surface in a complex with

MHC class I. It does not inhibit the surface expression of the

class I but inhibits its recognition by H-2Kb-restricted CTL.

Thus, m4 acts as a viral CTL evasion protein without affecting

expression of MHC-1. It is relevant to mention here that the

m152 /gp40-mediated inhibition of H-2D

b

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 surface

expression of MHC class I by specifically preventing their

terminal glycosylation, correct folding, and export from ER

[62]. The human herpesvirus 7 (HHV7) protein U21 associates

with the MHC class I inside the ER and directs its traffic

toward 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 their

recognition from virus-specific CTL. However, this strategy

also renders the infected cells susceptible to NK cell-mediated

killing. As stated earlier, MHC class I molecules, particularly

HLA-C, act as ligands for inhibitory NK cell receptors, e.g.,

KIR. A loss or a decreased expression of these HLA alleles on

the surface of virus-infected cells results in a loss of inhibition

of NK cells. To evade killing by NK cells and virus-specific

CTL, many viruses have evolved strategies to differentially

down-regulate MHC class I molecules. More specifically, they

down-regulate expression of HLA-A and -B, which mainly

present viral epitopes to CTL, but not the expression of HLA-C

and HLA-E, which act as ligands for inhibitory NK cell recep-

tors. HIV-1 uses this strategy via Nef protein, which binds

hypophosphorylated cytoplasmic tails in early forms of the

MHC class I antigens in the ER and redirects them from the

trans-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 interacts

selectively with the intracellular tyrosine motifs of different

HLA-A and HLA-B allotypes [66]. However, the HLA-C and

HLA-E do not have these tyrosine motifs and are not targeted

by Nef [67], which interacts with the subunit of the cellular

adaptor protein (AP) complex and recruits it to the MHC

cytoplasmic tails. This interaction with AP causes endocytosis

and retrograde trafficking of the MHC molecules from the cell

surface. They accumulate in clathrin-coated vesicles and are

targeted to degradation. However, the Nef mutants, which do

not interact with AP, can also down-regulate MHC expression

[64, 65]. Piguet et al. [68] have shown that Nef-mediated

down-regulation of the MHC antigens involves interaction be-tween the acidic domain of Nef and phosphofurin acidic cluster

sorting (PACS)-1, a molecule that localizes the cellular protein

furin to the trans Golgi network (TGN). According to their

model, Nef acts as a connector between the cytoplasmic tails of

the MHC antigens and PACS-1-dependent protein-sorting

pathway. In T cells, however, Nef mediates down-regulation of

the MHC molecules via disrupting its secretory pathway from

the TGN to the cell surface, whereas in non-T cells, these

effects of Nef on the transport of the MHC molecules to the cell

surface are less pronounced [64, 69]. Overall, Nef inhibits

expression of HLA-A and -B alleles on the cell surface and

protects the infected cells from CTL-mediated lysis [66, 69–71]. Indeed, the effects of Nef on MHC surface expression have

been shown to be important for the progression of the HIV

infection toward AIDS [72, 73].

As mentioned above, the KSHV proteins K3 and K5 have

the capacity to internalize the MHC class I antigens by Ub-

directed degradation from the cell surface. The two proteins

differ in their specificity for different MHC alleles. The K5

down-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 of

ICAM-1 and B7.2 in the virus-infected cells. This differential

down-regulation of the MHC molecules as well as of ICAM-1

and 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-regulate

the expression of MHC class I molecules from the surface of

the infected cells (Fig. 2; Table 2). They do so primarily to

evade host’s antiviral CTL responses. However, certain viruses

may in fact increase the expression of these molecules on the

surface of the infected cells, at least in the early phase of the

infection, 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 to

activate TAP functions via p53 induction [76]. This enhances




the TAP-dependent peptide import into the ER lumen and

increases the surface expression of MHC class I antigens. The

virus-infected cells consequently become more resistant to NK

cell-mediated killing. Activated NK cells seem to be important

in limiting viral replication, at least in the early phases of the

infection 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 of

professional APC is essential for presentation of foreign anti-

genic peptides to CD4 T lymphocytes. This presentation

results in the generation of antigen-specific CD4 Th cells.

The professional APC-like macrophages, DC and B cells take

up exogenous viral proteins by phagocytosis or endocytosis.

These cells generate antigenic peptides by protease action in

endosomal compartments that are presented by MHC class II

molecules, encoded by three different loci (HLA-DP, -DQ, and

-DR). The heterodimeric / chain constituting the MHC class

II is strongly associated with the invariant chain (Ii) in the ER

in a nonameric complex and represents an immature MHC-II

form. 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 of

defined cleavage intermediates, to generate class II-associated

Ii peptide, which occupies the peptide-binding groove of the

MHC class II until it is exchanged by an antigenic peptide in

the MIIC. This process of peptide loading is catalyzed by

HLA-DM and -DO (in B cells) inside the MIIC [77–80]. This

exchange leads to the constitution of a stable heterotrimeric

MCH class II peptide complex, mature MHC class II, which can

now reach the cell surface. By inhibiting the MHC class II

antigenic presentation at different levels, viruses interfere with the

generation of virus-specific CD4 T cells and hence, with the

induction of an effective antiviral cellular immune response.

Viruses encode proteins that may interfere with expres-

sion of MHC class II antigens (by down-regulating their

transcription and/or by disrupting their normal traffic within

the cells); loading of peptides onto these antigens; and their

presentation to naı ¨ve 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 viral

immune evasion. However, in recent years, many viral pro-

teins have been shown to interfere with antigen presentation

via MHC class II pathway.

At the transcriptional level, the HIV-1 Tat protein competes

with 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 with

CIITA for the cyclin T1/CD9 complex by binding to the same

site 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 class

I 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, Simian

immunodeficiency 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 inhibiting

interaction between the cyclic AMP response element-binding

protein (CREB)-binding protein (CBP) and the CIITA (ref. [81],

reviewed in ref. [82]). The IFN-mediated effects on the MHC II

expression are important for the induction of an effective

antiviral immune response.

Another way to subvert the antigen presentation is to alter

the intracellular trafficking of the class II antigens. In HSV-

infected cells, the viral glycoprotein B competes with the Ii

chain for binding with HLA-DR molecules. In addition, it also

associates with HLA-DM. It disturbs intracellular trafficking of

MHC class II and prevents them from reaching the cell surface

[83, 84]. The HIV Nef also impairs the membrane expression

of 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 accumulation

of multivesicular bodies (MVB) containing Nef, MHC class II,

and high amounts of Ii [85, 86]. It is interesting that HIV-1

recruits MVB machinery for budding in macrophages. The

HCMV 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- and

DM- from the ER, followed by their proteasome-mediated

degradation [88]. US3 binds to the newly synthesized MHC

class II / complexes in the ER and reduces their association

with Ii. This complex moves normally to the Golgi apparatus

but is not sorted efficiently to the MIIC, leading to a reduction

of the peptide-loaded, mature MHC class II complexes on the

cell 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 transmembrane

glycoprotein, which binds HLA-DR. This binding is essentialfor viral entry into DR-positive B cells. The viral protein also

associates with MHC class II molecules at various stages of

their maturation, e.g., immature --li heterotrimers and ma-

ture --peptide complexes, and inhibits antigen presentation

to CD4 T cells. It is interesting that a soluble form of gp42

is generated by proteolytic cleavage in the ER of the virus-

infected cells. The protein is secreted and inhibits HLA class

II-restricted antigen presentation to T cells by physically hin-

dering the MHC class II-TCR interactions. The transmembrane

and soluble forms of the protein are expressed in the EBV

genome-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 and

interferes 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 molecules

interact with their cognate ligands on immune cells. This

interaction plays an essential role in the presentation of viral

antigens to T cells and B cells and for the induction of an

effective antiviral cellular immunity. Costimulation is also

important for the efferent or effector phase of the immune

response. 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 if

stimulated only via CD16. Many viruses inhibit host’s antiviral

immune responses at the inductive and effector phases by

down-regulating the expression of costimulatory molecules on

host cells. For example, the KSHV-K5 down-regulates surface

expression of the costimulatory molecules ICAM-1 and B7.2 on

the surface of virus-infected cells [93, 94]. The Myxomavirus

homologue of the K5, M153R, is also a Ub ligase. It targets

MHC class I antigens and CD4 and internalizes and redirects

them to proteasomal degradation. The M153R-mediated deg-

radation is dependent on the presence of lysine residues in the

cytoplasmic tails of the target proteins [55, 95]. The adenovirus

oncoprotein E1A decreases the expression of another adhesion

molecule lymphocyte function-associated antigen-3 on the sur-

face of Ad5- and Ad12-transformed cells [96]. It is noteworthy

that Nef, Vpu, and Gp160 of HIV-1 reduce surface expression

of CD4 and CD28 on the virus-infected cells. Therefore, HIV-infected cells cannot provide proper costimulation when they

interact with virus-specific T cells [71, 85].

The induction of a virus-specific CTL response to HCMV

and MCMV represents the main and most efficient effector

function for the control of these pathogens [97–100]. The

HCMV main tegument protein pp65 and the immediate early

protein-1 (IE1) are the major targets for the antiviral CTL

raised against HCMV-infected cells [97]. The pp65 has kinase

activity. 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 is

interesting that the HCMV-specific CTL response is dominatedby the pp65. This protein was recently shown to act as a ligand

for NKp30, an activating NK cell receptor. The binding of the

protein to the receptor causes dissociation of the receptor-

associated signaling component, the chain [102], which acts

as a signaling component for several other activating receptors

found on the surface of NK and T cells. Thus, the protein may

cause 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 the

lymphocytes 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 an

important role in immune regulation by secreting immunolog-

ically important cytokines and chemokines, e.g., including

IFN-, TNF-, macrophage-inflammatory protein-1 (MIP-

1), and MIP-1. The NK cell-secreted IFN and TNF- may

also control viral replication by noncytolytic mechanisms. NK

cells and mature DC reciprocally activate each other. As stated

earlier, NK cells are usually activated in early phases of a viral

infection. Activated NK cells are important in killing virus-

infected cells, especially before the generation of virus-specific

CTL and antibodies. Unlike T and B cells, which express




well-defined, clonally distributed antigen receptors, NK cells

activity is controlled by a diverse array of activating and

inhibitory receptors and coreceptors, which bind different li-

gands present on the surface of a target cell and send activating

and inhibitory signals to the NK cell. The balance between the

inhibitory and activating signals determines whether the NK

cells would kill the target cell or be inhibited from killing it. In

recent years, a great deal has been learned about these recep-

tors and their ligands [11, 104]. The known NK cell receptors

and coreceptors as well as their ligands are given in Table 1.

The most important ligands, which bind inhibitory receptors on

NK cells and inhibit their activity, are MHC class I antigens,

especially HLA-C and -E. Most body cells and tumor cells

usually express ligands for some activating NK cell receptors.

NK cells would kill these cells by default unless they are

inhibited by the engagement of their inhibitory receptors. The

presence of MHC class I antigens on the surface of a cell

usually makes it resistant to NK cell-mediated killing.

As NK cells could play an important role in controlling virus

replication, viruses have evolved many strategies to evade

host’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-regulation

usually 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-regulate

HLA-A and -B but not HLA-C and -E. As HLA-A and -B

mainly present virus-derived antigenic peptides to CTL, their

down-regulation protects virus-infected cells from CTL-medi-

ated killing. Conversely, HLA-C and -E mainly act as ligands

for inhibitory NK cell receptors by maintaining their normal

expression on the surface of virus-infected cells; viruses tend

to maintain their resistance to NK cells. This way, these viruses

can evade CTL and maintain resistance of the virus-infectedcell to NK cells.

The viruses may also evade NK cell responses by increasing

the 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 -C

allotypes. The HCMV protein UL-40 acts as a source of the

peptides that can bind HLA-E. Thus, by supplying a source of

HLA-E-specific peptides, UL-40 stabilizes the expression of

HLA-E on the surface of HCMV-infected cells [105–108].

HLA-E inhibits NK cell activation by interacting with the

inhibitory receptor CD94/NKG2A. As mentioned earlier,

HCMV encodes several proteins to reduce the expression of

MHC class I on the surface of the virus-infected cells. As

HLA-E needs peptides derived from the signal sequences of

other MHC allotypes, the decreased expression of MHC class

I would also have decreased the expression of HLA-E on the

surface. By encoding UL-40, HCVM compensates for the loss

of peptide pool for HLA-E. More recently, an immunodominant

CTL epitope derived from the HIV protein p24 was also shown

to bind HLA-E and increase the expression of this MHC

antigen on the cell surface [109]. Thus, HIV may also evade

NK 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, which

forms heterodimers with 2m and can bind endogenous pep-

tides. In addition to decreasing the expression of other MHC

molecules 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 may

therefore also inhibit activation of these cell types.

When under stress or infected with a virus, the cells express

certain stress-inducible proteins MIC-A, MIC-B, and

ULBP1–4. These de novo expressed proteins interact with the

NK cell receptor NKG2D and trigger NK cell activity. It is

interesting that the NK cell activation mediated by NKG2D is

not inhibited via inhibitory KIR. Moreover, NKG2D is also

expressed on the surface of activated macrophages and certain

T cells and is involved in the activation and costimulation of these cells. The HCMV-encoded protein UL16 binds to MIC-B

and ULBP1 and -2 and decreases their cell surface expression

[112–114]. This inhibits killing of the virus-infected cells via

NKG2D. 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 activation

EBV EBNA-1 Novel peptides for HLA-A, -B 2NK cell activation via KIR3DLHCMV pp65 2NK cell activation via NKp30UL40 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-like

transcript-1. The arrows 2 and 1 indicate increase and decrease, respectively.




glycoproteins distantly related to the MHC class I family. It is

interesting that these proteins were first identified by their

ability to bind to the HCMV protein UL16 [115]. The UL16

binds the NKG2D ligands intracellularly and redirects their

intracellular 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 UL141

gene product blocks the surface expression of CD155, which is

known as a ligand for the activating NK cell receptors DNAM-1

(CD226) and TACTILE (CD96) [117]. UL141 is not the only

HCVM 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 function

of another activating NK cell receptor NKp30. The protein

causes dissociation of the receptor from the signal-transducing

partner, the chain [102].

Like HCMV, the MCMV has also developed several strate-

gies to evade host’s NK cell responses (Table 3). Its m155 gene

product can subvert the NK cell cytotoxicity by down-regulat-

ing H60, which is a stress-inducible protein that acts as a

specific, 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 m152

binds H60 and Rae-1, whereas the m145 can bind and se-

quester MULT-1 intracellularly [119, 120]. Like H60, Rae-1

and MULT-1 act as ligands for NKG2D for mouse NK cells.

These examples clearly show that HCMV and MCVM have

developed strategies to inhibit NKG2D-mediated NK cell kill-

ing of the virus-infected cells. These strategies may also inhibit

macrophages and prevent costimulation of T cells via this

activating receptor.

A great deal has been learned about the role of the MCMV

protein 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 is

an activating NK cell receptor, whereas Ly49I is an inhibitory

one. The MCVM-resistant mouse strains express Ly49H, and

MCVM-susceptible strains express Ly49I on their NK cells.

The interaction of m157 with Ly49-positive NK cells leads to

their activation, proliferation, and release of various cytokines

and chemokines. The passage of the m157-positive MCMV in

resistant Ly49-positive mice leads to mutations in m157 pro-

tein and escape from the NK cell-mediated control of the viral

replication. Wild-type MCVM also shows mutations in this

viral 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 as

a complex with a variety of receptors on the surface of different

cell types including T, B, and NK cells. The effects of CD81

cross-linking with specific antibodies may vary depending on

the 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, which

is essential for cleaving HCV-encoded polyproteins into bio-

logically active proteins. The protease was shown to inhibit

activation (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 induction

of type I IFN as well as in the IFN-mediated antiviral effects.

As stated above, one of the effects of these IFN is to activate

NK cells; HCV can evade NK cell activation by preventing

IRF-3 activation. Other viruses also use similar strategies to

inhibit NK cell activation. For example, the Ebola and Rabies

virus-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 unique

strategy to inhibit host’s NK cell responses. The viral protein

EBNA-3A supplies peptides, which can bind certain HLA-A

allotypes [130]. These HLA-peptide complexes are recognized

specifically by the inhibitory NK cell receptors KIR3DL2. This

recognition inhibits NK cells from killing EBV-infected/trans-

formed host cells. It is interesting that a variety of peptides

derived from different other human viruses, which bound these

HLA 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-mediated

innate immunity against this virus.

Moreover, certain viruses encode proteins, which are MHCclass I homologues and can inhibit NK cell activation. The

HCMV encodes MHC class I -chain homologue UL18, which

can complex with 2m and bind endogenous peptides. It is

resistant to down-regulation by the viral proteins US2, -3, -6,

and -11 [41, 131–133]. Similarly, the MCMV encodes a MHC

class I homologue, m144, which confers protection from NK

cell effector functions, even when classical MHC class I anti-

gens are down-regulated from the surface of the virus-infected

cells. In vivo studies have shown that m144-expressing MHC

class I-deficient lymphoma cells can inhibit activation and

accumulation 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 certain

inhibitory NK cell receptors.

Evasion from CTL by antigenic variation

This is an important strategy evolved by RNA viruses, which

have small genomes and cannot afford to encode many different

immune-evasion proteins. Because of poor editing functions of

the virus-encoded polymerases and a high rate of virus repli-

cation, several point mutations occur at random in structural

and 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 immune

response 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 amino

acid sequence of the epitopes recognized by the CTL. Under

pressure from virus-specific CTL, the viruses carrying these

mutations (escape mutants) accumulate in the infected indi-

viduals. In a similar manner, viruses may mutate to evade

virus-specific CD4 T cells and virus-neutralizing antibodies.

When the infected host develops immune responses to the

escape mutants, new escape mutants emerge, which can evade




host’s antiviral immune responses. Furthermore, viruses may

also undergo antigenic variation by recombination between

diverse 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 the

host’s immune responses until host’s ability to mount an im-

mune response is exhausted. All viral epitopes can undergo

mutations unless the mutation is in a highly conserved region

and compromises a key function of the protein. The mutant

viruses may infect another host, and the mutations may persist

if the new host does not restrict and present the mutated

epitope. The mutated epitopes, at least in vitro, may act as

altered peptide ligands and anergize or cause apoptosis of the

virus-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 been

documented that human populations are selectively accumu-

lating viruses with mutated epitopes, which are presented by

the most prevalent HLA allotypes. Nevertheless, the persis-

tence of many epitope-encoding HIV sequences has been

documented in the infected individuals having strong epitope-

specific CTL responses, suggesting a complex relationship

between immune evasion and antigenic variation Large DNAviruses, which cause chronic infections, such as EBV and

HCMV, have also been documented to use this strategy to

evade 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 genome

segments between different viruses. Newly emerged recombi-

nant viruses can evade the immunity, which is prevalent in the

host. Such recombinant influenza viruses have caused great

havoc in the human history. The influenza virus that caused the

1918 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 the

host cells is called latency. Viruses may evade immune re-

sponses of the host by becoming “latent” and invisible to the

immune system. During latency, viruses may infect nonpermis-

sive or semipermissive cells of the host and express only a

minimum number of viral genes, which are just necessary to

maintain the virus in the cells. The ubiquitous human pathogen

EBV represents a classic example of viral latency [141]. The

virus 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. The

virus 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 cells

but persists as latent infection with little gene expression in

sensory neurons of Trigeminal ganglia, which do not express

MHC antigens [142]. The virus expresses only one gene, the

latency-associated transcript gene, which inhibits viral repli-

cation. Upon proper stimuli, such as immunosuppression,

trauma, or exposure to sun or ultraviolet radiation, the virus

may activate itself and descend down axons of the neurons and

infect epithelial cells. Similarly, Herpes zoster virus becomes

latent in dorsal root ganglions of the spinal cord. Another

herpesvirus, HCMV, persists for long periods of time in kidney,

retina, and bone marrow. HIV-1 is known to persist as a latent

transcriptionally inactive provirus in the host cell’s genome in

long-lived, resting CD4 memory T cells [143]. These cells

may lack virus-needed transcription factors. The virus may

also persist in the brain, which is protected by blood brain

barrier from infiltration of lymphocytes. These cells and tissues

serve 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 immune

cells, which play a key role in orchestrating antiviral immune

responses. For example, HIV-1 infects CD4 T cells. The

depletion of these cells is a hallmark of HIV-induced AIDS. It

has been shown that HIV-specific CD4 T cells are more

susceptible to HIV infection than HCMV-specific CD4 T

cells, as the former cells preferentially migrate to the sites of

HIV infection [144]. CD4 T cells play an important role in

the generation of virus-specific CTL and antibodies. The lack

of help from CD4 T cells is probably one of the reasons for

incomplete differentiation of HIV-specific CTL in HIV-in-

fected individuals [145, 146]. Consequently, these CTL are

compromised in their cytotoxic abilities and are unable to clear

the infection [147]. Many viruses, e.g., the reovirus and mea-

sles virus, infect DC and induce the expression of TRAIL and

FasL on their surface [148]. Such DC cannot present antigens

and prime T cells for the generation of virus-specific CTL.

Instead, they kill interacting T, B, and NK cells via Fas/FasL

and TRAIL/DR interactions (Fig. 1). The virus-infected DCmay in fact induce immunosuppression instead of an antiviral

immune response. The human pathogen HSV-1 infects and

induces 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 the

mRNA level. The virus also increases the expression of TNF-

and TRAIL in these cells. These ligands induce apoptosis in

the virus-infected DC [149]. The HIV protein Nef was shown to

bind CXC chemokine receptor 4 and induce apoptosis of

CD4 T cells [150]. Another HIV protein Vpr inhibits DC

maturation and impairs their ability to activate virus-specific

CTL 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 and

controlled process of degradation of its protein and DNA

contents by its own enzymes [152]. It is a relatively silent and

noninflammatory process. The cells may undergo apoptosis

through an extrinsic or intrinsic pathway. The extrinsic path-

way is activated when external factors such as TNF-, FasL, or

TRAIL bind to their specific receptors, so-called death recep-




tors or DR, a family of TNFR-related proteins expressed on the

cell 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 the

DED of procaspase 8 or 10 (also called FLICE). This results in

the proteolytic cleavage and activation of these caspases. The

intrinsic 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-1

and procaspase-9, resulting in the activation of the latter.

DIABLO binds and inhibits cellular IAP and allows activated

caspases to mediate their effects. Cells may undergo apoptosis

through this pathway when subjected to irreparable DNA dam-

age, viral infections, or physical and chemical insults. There is

an active cross-talk between the two pathways. The activation

of one may lead to activation of the other pathway. A critical

step in this cross-talk is the cleavage of the proapoptotic

protein Bid by caspase-8, which is activated by the extrinsic

pathway. The cleaved Bid promotes cytochrome c release and

activation of the intrinsic pathway of apoptosis. Both pathways

lead 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 principal

mechanism for killing virus-infected cells. They do so by

releasing certain cytotoxic molecules, such as TNF-, perforin,

and granzymes, as well as by engaging DR on the surface of the

virus-infected cells. It is noteworthy that the granzyme B,

which is released by CTL and NK cells and is endocytosed by

the target cells, can activate several caspases directly.

Viruses encode various proteins to modulate apoptosis to

their own advantage (Table 4). They inhibit premature apo-

ptosis of the virus-infected cells (before replication of the virus

has occurred). After completion of the viral replication, virusesmay promote apoptosis to disseminate progeny virus without

causing inflammatory responses. Viral antiapoptotic strategies

also help the virus evade CTL and NK cell-mediated killing of

the virus-infected cells.

The host cells respond to many viral infections by inducing

and activating the proapoptotic antioncoprotein p53. It is one

of the main sensors of the cell for activating the intrinsic

pathway 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 antiapoptotic

gene Bcl-2. Upon its activation, the virus-infected cell could

die before the virus has completed its replication. To evade this

premature apoptosis of the infected cells, many viruses encode

proteins 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 protein

of Hepatitis B virus [153]. The human T-lymphotropic virus

protein Tax and the EBV oncoprotein latent membrane protein

1 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 human

cancer cells efficiently. These observations have led to the

development of a new class of therapeutic oncolytic viruses for

treating a variety of cancers [156]. Oncogenic viruses also use

another strategy to block apoptosis by the intrinsic pathway.

They encode Bcl-2 homologues, which prevent the release of

cytochrome c from mitochondria. The examples include E1B-19K of adenoviruses, the BHRF1 and bronchoalveolar lavage

fluid-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, which

has 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, which

phosphorylates Bad and prevents Bad-induced activation/am-

plification of apoptosis [158].

Many viruses can escape the apoptosis mediated via the

extrinsic 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 of

action of vFLIP is shown in Figure 4. Many -herpesviruses,

including the HHV8, herpesvirus saimiri, equine herpesvirus

2, 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 the

cellular ortholog of the vFLIP have also been identified (see

below). They compete with the adaptor FLICE and regulate

apoptosis [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-death

suppressors [163]. The vFLIP can also inhibit apoptosis byincreasing the expression of nuclear factor (NF)-B through

their interactions with different adaptor proteins, including

TNFR-associated factor-2, NF-B-inducing kinase, and inhib-

itor of IB kinase-2 [164]. The cellular ortholog of vFLIP has

been cloned, and it generates two protein forms as a result of

alternate splicing: a short, 26 kD, and a long, 55 kD, form.

Both forms can delay or inhibit apoptosis by recruitment to the

DISC [159].

Caspases are cytosolic proteins with a cysteine-based, as-

partate-directed protease activity. They are involved in the

transduction 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 of FLICE 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 Nef

promotes Bad phosphorylation.7. Inhibiting p53 activation, e.g., SV40 large T antigen, adenovirus

E1B.8. Interfering with intracellular signaling molecule, e.g., Nef

inhibits 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 the

apoptosis. Many viruses encode proteins, viral IAP (vIAP),which inhibit the enzymatic activity of caspases [165, 166]. For

example, the baculovirus p35 gene product inhibits Fas and

TNF-induced apoptosis by inhibiting caspases [167]. The HSV

gene, US5-encoded glycoprotein gJ, has been shown to inhibit

Fas and granzyme B-mediated apoptosis by blocking activation

of caspase-3 [168]. All poxvirus genomes encode vIAP to

inhibit apoptosis. The cowpox virus protein, the CrmA, can

inhibit several caspases, probably via covalent modification of

caspase 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 the

effector (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 from

apoptosis by interfering with an essential signaling molecule,

the ASK1, which is a serine/threonine kinase involved in the

formation of a key signaling intermediate in the FasL- and

TNF--induced death pathway [174]. This protects HIV-in-

fected cells from apoptosis as a result of the cis ligation of Fas

by FasL, as the virus increases the expression of Fas and FasL

on the surface of the infected cells.

Some viruses can evade host’s cellular immune response by

regulating the expression of DR ligands to their own advantage.

The measles virus induces the expression of TRAIL in infected

human monocyte-derived DC (Fig. 1). These DC become cy-totoxic and induce immunosuppression by killing interacting T

cells 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 and

increases 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 counter

and evade host’s antiviral immune response but also to induce

immunosuppression in the infected host.

Adenoviruses protect virus-infected cells from apoptosis by

inhibiting the expression of DR on the cell surface. The E3

region of all adenoviruses encodes three integral membrane

viral proteins: E3-10.4K, E3-14.5K, and E3-6.7K. They areexpressed as heteromeric complexes, receptor internalization

and degradation (RID) complexes, which reduce the membrane

expression of Fas and receptors for TRAIL and epithelial

growth factor [178–181]. The loss of these receptors leads to

protection 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 I

antigens [179]. The complexes redirect intracellular trafficking

of the DR to late endosomes for degradation. The SIV protein

Nef increases the expression of FasL on the surface of the

virus-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 HCMV

viral 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 increases

the expression of FasL and TNF- in DC. Exogenous Nef also

triggers apoptosis of CD8 T cells by activating caspase-8.

Collectively, these effects abrogate the ability of DC to prime

and activate alloreactive CD8 T cells. The cells rather be-

come anergic and show decreased proliferation, cytoxocity, and

IFN- production [184]. The viral protein Tat induces expres-

sion of TRAIL in primary human macrophages [185]. HIV also

directly promotes apoptosis of immune cells to evade host’s

antiviral immune responses [186]. The Tat protein acts as a

proapoptotic protein by up-regulating the sensitivity of CD4

T cells to Fas-mediated apoptosis, mainly by increasing the

activity and expression of caspase-8 [187, 188]. Another HIV

protein Vpu also enhances the susceptibility of CD4 T cells

to the Fas-induced apoptosis [189]. By these mechanisms,

HIV-1 manipulates the apoptotic machinery to its advantage in

infected and uninfected cells. It promotes unresponsiveness

and death of neighboring, uninfected immune cells but protects

the 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 of

various cell types involved in the induction of immune re-

sponse and inflammation in vial infections. By communicating

between 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 by

stimulating production of a variety of cytokines and chemo-

kines. It is not surprising that viruses have developed several

strategies to counter these responses. These strategies include

encoding inhibitors, decoy receptors, or modified viral versions

of these soluble mediators (summarized in Table 5; ref. [191]).The poxviruses and herpesviruses modulate host’s cytokine

responses by producing proteins, which act as mimics for

cytokines 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 also

encodes an IL-10 homologue, which shares 27% sequence

homology with human IL-10 [193]. Both the vIL-10s are highly

immunosuppressive and can inhibit production of IFN- and

TNF- 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 II

antigens and costimulatory molecules ICAM-1, CD80, and

CD86 but increase the expression of HLA-G on human PBMC

[194, 195]. The two viruses seem to have usurped the human

IL-10 gene by different mechanisms [195]. They have modified

the 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 recently

shown to have IL-10-like activities [196].

Concerning chemokines, the herpesviruses such as KSHV,

HHV6, and HCMV encode proteins, which bear sequence

homology to human chemokines MIP-1 [191]. Certain virus-

encoded chemokines may evade immune responses by acting

as antagonists (e.g., vMIP-2 of KSHV), and others may facili-

tate virus spread by acting as agonists (e.g., U83 protein of

HHV6). Furthermore, certain virus-encoded chemokine-like

proteins may skew the immune response by chemoattracting

TH-2 type CD4 T cells (e.g., vMIP-1, -2, and -3 of KSHV).

Some viruses may encode proteins, which have no sequence

homology 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 via

the fractalkine receptor [197].

The poxviruses and herpesviruses encode proteins, which

are similar in sequence to the extracellular ligand-binding

domains of certain cytokine or chemokine receptors but lack

their intracytoplasmic tails. Functionally, they act as decoy

receptors and neutralize the bound cytokines and chemokines

of the host, as they can bind the cytokine or the chemokine but

cannot transmit signals. A good example is the cowpox, which

encodes at least four different TNFR [191, 198]. Similarly,

viruses have targeted other cytokine receptors (e.g., including

IL-1R, 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, and

US27 proteins of KSHV, HCMV, and HHV6, respectively. The

virus-encoded chemokine receptors are expressed on the sur-

face of the infected cells, and their role in immune evasion is

not yet fully understood (reviewed in ref. [191]).

In addition to encoding decoy receptors, viruses also encode

homologues of the cellular proteins that can bind and inhibit a

cytokine. The certain poxviruses such as cowpox virus, ec-

tromelia virus, and vaccinia virus encode a soluble protein

vIL-18BP, which like its cellular homologue, binds and neu-

tralizes the biological activity of IL-18 [199]. It is noteworthy

that 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 and

prevents IFN from binding to its receptors. Similar to the

virus-encoded cytokine-binding proteins, viruses also encode

proteins that can bind chemokines and neutralize them. The

myxoma virus encodes M-T7 [or virus chemokine-binding pro-

tein 1 (vCKBP-1)], which can bind and inactivate several

chemokines. However, the poxvirus-encoded chemokines do

not bind to M-T7. The vCKBP-2 binds to C–C chemokines and

is encoded by myxoma and vaccinia viruses. The third

vCKBP-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 mutant

MHV was found to be less pathogenic in mice [200].

The cowpox virus CrmA inhibits caspase-1, also called

IL-1-converting enzyme, which is needed to cleave precursor,

immature IL-1 and IL-18 into biologically active, mature

cytokines [201].

Mimicking FcR

Viruses may also use other strategies to evade host’s cellular

immune responses. The MCMV, HCMV, and HSV-1 encode atleast one protein, which mimics a FcR [202, 203]. The FcR

homologues are thought to prevent macrophage activation from

immune complexes and protect virus-infected cells from NK

cell 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 site

distinct from the antigen-binding groove on APC and to par-

ticular variable regions of the -chain of the TCR. Each SA

binds 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 about

bacterial SA, more than 40 of which have been identified

(reviewed in ref. [204]). A SA-encoding human endogenous

retrovirus (HERV)-K18 has been identified in humans. The

provirus is located on human chromosome 1 in the first intron

of CD48 in reverse orientation and has three alleles. The

truncated envelope protein of the virus acts as a SA, which can

bind V-7- and V13-containing TCR (ref. [205]). Several

studies suggest that viruses, such as EBV, HIV, HCMV, and

rabies virus, encode SA. These conclusions were drawn, as the

individuals 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 the

SA encoded by these viruses has remained elusive. It is

interesting that Sutkowski et al. [207] have demonstrated that

EBV does not encode any SA per se; it rather activates the

SA-encoding HERV-K18 at the transcriptional level. These

results explain the expansion of V13-positive T cell subsets

in EBV-infected individuals. Apart from EBV, IFN- has also

been demonstrated to activate this endogenous retrovirus in

human PBMC (ref. [208]). It is quite possible that the SA-like

activities observed in other human viral infections might also

be a result of their activation of some unknown SA-encoding

endogenous 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. They

may also use the T cell-secreted cytokines and growth factors

to propagate their own target cells. For example, the mouse

mammary 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 to

infect B cells. Because of their ability to activate a large

number of T cells with diverse antigenic specificities, SA may

predispose 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 evade

host’s immune responses. These strategies are as diverse as the

viruses themselves. In general, each virus uses multiple strat-egies for immune evasion. Large DNA viruses can afford to

encode multiple proteins that target different aspects of the

immune response. Small RNA viruses mainly rely on antigenic

variability as the principal immune evasion mechanism. The

down-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 controlling

the replication of these viruses in the infected host. However,

as exemplified by HIV-1, HCV, HCMV, and MCMV, the

viruses also have to develop mechanisms to avoid being killed

by NK cells. In fact, we are only beginning to understand the

immunobiology of these cells. As many viruses differentially

down-regulate HLA (-A and -B but not -C) molecules to

simultaneously evade killing of the virus-infected cells by CTL

and NK cells, the viral epitopes presented by HLA-C may be

used for vaccine purposes. Efforts should be directed at devel-

oping reagents, which could block the action of the viral

proteins 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 represent

ideal molecular targets for developing novel antiviral drugs.

Understanding viral immune evasion mechanisms allows us a

better understanding of the host parasite interactions and their

coevolution. This knowledge may also enable us to devise

rational strategies for countering these evasion mechanisms.

ACKNOWLEDGMENTS

A. A. is the recipient of a “Chercheur-boursier senior” award

from 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 discussions

on the subject and the Canadian Institutes of Health Research

for support. We regret that due to space limitations, all studies

on the subject could not be cited.

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