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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 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 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
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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
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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.
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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.
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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,
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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
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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.
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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
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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.
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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
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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-
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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.
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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
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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.
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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.
REFERENCES
1. Kurt-Jones, E. A., Popova, L., Kwinn, L., Haynes, L. M., Jones, L. P.,Tripp, R. A., Walsh, E. E., Freeman, M. W., Golenbock, D. T., Anderson,L. J., Finberg, R. W. (2000) Pattern recognition receptors TLR4 andCD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1,398–401.
2. Pasare, C., Medzhitov, R. (2005) Toll-like receptors: linking innate andadaptive immunity. Adv. Exp. Med. Biol. 560, 11–18.
3. Liu, Y. J. (2005) IPC: professional type 1 interferon-producing cells andplasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23 , 275–306.
30 Journal of Leukocyte Biology Volume 79, January 2006 http://www.jleukbio.org
8/12/2019 Viral Strategies for Evading Antiviral Cellular Immune Respo
http://slidepdf.com/reader/full/viral-strategies-for-evading-antiviral-cellular-immune-respo 16/20
4. Siegal, F. P., Kadowaki, N., Shodell, M., Fitzgerald-Bocarsly, P. A.,Shah, K., Ho, S., Antonenko, S., Liu, Y. J. (1999) The nature of theprincipal type 1 interferon-producing cells in human blood. Science 284,
1835–1837.5. Gatti, E., Pierre, P. (2003) Understanding the cell biology of antigen
presentation: the dendritic cell contribution. Curr. Opin. Cell Biol. 15,
468–473.6. Del Prete, G. (1998) The concept of type-1 and type-2 helper T cells and
their cytokines in humans. Int. Rev. Immunol. 16, 427–455.7. Gulzar, N., Copeland, K. F. (2004) CD8 T-cells: function and response
to HIV infection. Curr. HIV Res. 2, 23–37.8. Hahn, Y. S. (2003) Subversion of immune responses by hepatitis C virus:
immunomodulatory strategies beyond evasion? Curr. Opin. Immunol. 15,
443–449.9. Ahmad, A., Menezes, J. (1996) Antibody-dependent cellular cytotoxicity
in HIV infections. FASEB J. 10, 258–266.10. Ahmad, A., Ahmad, R. (2003) HIV’s evasion of host’s NK cell response
and novel ways of its countering and boosting anti-HIV immunity. Curr. HIV Res. 1, 295–307.
11. Lanier, L. L. (2005) NK cell recognition. Annu. Rev. Immunol. 23,
225–274.12. Guidotti, L. G., Chisari, F. V. (2001) Noncytolytic control of viral
infections by the innate and adaptive immune response. Annu. Rev. Immunol. 19, 65–91.
13. Petersen, J. L., Morris, C. R., Solheim, J. C. (2003) Virus evasion of MHCclass I molecule presentation. J. Immunol. 171, 4473–4478.
14. Vossen, M. T., Westerhout, E. M., Soderberg-Naucler, C., Wiertz, E. J.(2002) Viral immune evasion: a masterpiece of evolution. Immunogenet-ics 54, 527–542.
15. Ploegh, H. L. (1998) Viral strategies of immune evasion. Science 280,248–253.
16. Hewitt, E. W. (2003) The MHC class I antigen presentation pathway:strategies for viral immune evasion. Immunology 110, 163–169.
17. Piguet, V. (2005) Receptor modulation in viral replication: HIV, HSV,HHV-8 and HPV: same goal, different techniques to interfere withMHC-I antigen presentation. Curr. Top. Microbiol. Immunol. 285, 199–217.
18. Brown, J. A., Howcroft, T. K., Singer, D. S. (1998) HIV Tat proteinrequirements for transactivation and repression of transcription are sep-arable. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 17, 9–16.
19. Kamp, W., Berk, M. B., Visser, C. J., Nottet, H. S. (2000) Mechanismsof HIV-1 to escape from the host immune surveillance. Eur. J. Clin. Invest. 30, 740–746.
20. Kanazawa, S., Okamoto, T., Peterlin, B. M. (2000) Tat competes withCIITA for the binding to P-TEFb and blocks the expression of MHC class
II genes in HIV infection. Immunity 12, 61–70.21. Ashrafi, G. H., Tsirimonaki, E., Marchetti, B., O’Brien, P. M., Sibbet,
G. J., Andrew, L., Campo, M. S. (2002) Down-regulation of MHC class Iby bovine papillomavirus E5 oncoproteins. Oncogene 21, 248–259.
22. Ashrafi, G. H., Haghshenas, M. R., Marchetti, B., O’Brien, P. M., Campo,M. S. (2005) E5 protein of human papillomavirus type 16 selectivelydownregulates surface HLA class I. Int. J. Cancer 113, 276–283.
23. Yin, Y., Manoury, B., Fahraeus, R. (2003) Self-inhibition of synthesisand antigen presentation by Epstein-Barr virus-encoded EBNA1. Science301, 1371–1375.
24. Lybarger, L., Wang, X., Harris, M., Hansen, T. H. (2005) Viral immuneevasion molecules attack the ER peptide-loading complex and exploitER-associated degradation pathways. Curr. Opin. Immunol. 17, 71–78.
25. Koppers-Lalic, D., Reits, E. A., Ressing, M. E., Lipinska, A. D., Abele,R., Koch, J., Marcondes-Rezende, M., Admiraal, P., van Leeuwen, D.,Bienkowska-Szewczyk, K., Mettenleiter, T. C., Rijsewijk, F. A., Tampe,
R., Neefjes, J., Wiertz, E. J. (2005) Varicelloviruses avoid T cell recog-nition by UL49.5-mediated inactivation of the transporter associated withantigen processing. Proc. Natl. Acad. Sci. USA 102, 5144–5149.
26. Ahn, K., Meyer, T. H., Uebel, S., Sempe, P., Djaballah, H., Yang, Y.,Peterson, P. A., Fruh, K., Tempe, R. (1996) Molecular mechanism andspecies specificity of TAP inhibition by herpes simplex virus ICP47. EMBO J. 15, 3247–3255.
27. Bennett, E. M., Bennink, J. R., Yewdell, J. W., Brodsky, F. M. (1999)Cutting edge: adenovirus E19 has two mechanisms for affecting class IMHC expression. J. Immunol. 162, 5049–5052.
28. Lehner, P. J., Cresswell, P. (1996) Processing and delivery of peptidespresented by MHC class I molecules. Curr. Opin. Immunol. 8, 59–67.
29. Hengel, H., Flohr, T., Hammerling, G. J., Koszinowski, U. H., Momburg,F. (1996) Human cytomegalovirus inhibits peptide translocation into theendoplasmic reticulum for MHC class I assembly. J. Gen. Virol. 77,
2287–2296.
30. Ahn, K., Gruhler, A., Galocha, B., Jones, T. R., Wiertz, E. J., Ploegh,H. L., Peterson, P. A., Yang, Y., Fruh, K. (1997) The ER-luminal domainof the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity 6, 613–621.
31. Hengel, H., Koszinowski, U. H. (1997) Interference with antigen pro-cessing by viruses. Curr. Opin. Immunol. 9, 470–476.
32. Lehner, P. J., Karttunen, J. T., Wilkinson, G. W., Cresswell, P. (1997)The human cytomegalovirus US6 glycoprotein inhibits transporter asso-ciated with antigen processing-dependent peptide translocation. Proc. Natl. Acad. Sci. USA 94, 6904–6909.
33. Kyritsis, C., Gorbulev, S., Hutschenreiter, S., Pawlitschko, K., Abele, R.,Tampe, R. (2001) Molecular mechanism and structural aspects of trans-porter associated with antigen processing inhibition by the cytomegalo-
virus protein US6. J. Biol. Chem. 276, 48031–48039.34. Hewitt, E. W., Gupta, S. S., Lehner, P. J. (2001) The human cytomega-
lovirus gene product US6 inhibits ATP binding by TAP. EMBO J. 20,387–396.
35. Ulbrecht, M., Hofmeister, V., Yuksekdag, G., Ellwart, J. W., Hengel, H.,Momburg, F., Martinozzi, S., Reboul, M., Pla, M., Weiss, E. H. (2003)HCMV glycoprotein US6 mediated inhibition of TAP does not affectHLA-E dependent protection of K-562 cells from NK cell lysis. Hum. Immunol. 64, 231–237.
36. Wiertz, E. J., Jones, T. R., Sun, L., Bogyo, M., Geuze, H. J., Ploegh, H. L.(1996) The human cytomegalovirus US11 gene product dislocates MHCclass I heavy chains from the endoplasmic reticulum to the cytosol. Cell84, 769–779.
37. Schust, D. J., Tortorella, D., Seebach, J., Phan, C., Ploegh, H. L. (1998)Trophoblast class I major histocompatibility complex (MHC) productsare resistant to rapid degradation imposed by the human cytomegalovirus
(HCMV) gene products US2 and US11. J. Exp. Med. 188, 497–503.38. Tortorella, D., Story, C. M., Huppa, J. B., Wiertz, E. J., Jones, T. R.,Bacik, I., Bennink, J. R., Yewdell, J. W., Ploegh, H. L. (1998) Disloca-tion of type I membrane proteins from the ER to the cytosol is sensitiveto changes in redox potential. J. Cell Biol. 142, 365–376.
39. Machold, R. P., Wiertz, E. J., Jones, T. R., Ploegh, H. L. (1997) TheHCMV gene products US11 and US2 differ in their ability to attackallelic forms of murine major histocompatibility complex (MHC) class Iheavy chains. J. Exp. Med. 185, 363–366.
40. Wiertz, E. J., Tortorella, D., Bogyo, M., Yu, J., Mothes, W., Jones, T. R.,Rapoport, T. A., Ploegh, H. L. (1996) Sec61-mediated transfer of amembrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432–438.
41. Park, B., Oh, H., Lee, S., Song, Y., Shin, J., Sung, Y. C., Hwang, S. Y.,Ahn, K. (2002) The MHC class I homolog of human cytomegalovirus isresistant to down-regulation mediated by the unique short region protein(US)2, US3, US6, and US11 gene products. J. Immunol. 168, 3464–3469.
42. Lopez-Botet, M., Angulo, A., Guma, M. (2004) Natural killer cell recep-tors for major histocompatibility complex class I and related molecules incytomegalovirus infection. Tissue Antigens 63, 195–203.
43. Gewurz, B. E., Gaudet, R., Tortorella, D., Wang, E. W., Ploegh, H. L.,Wiley, D. C. (2001) Antigen presentation subverted: structure of thehuman cytomegalovirus protein US2 bound to the class I moleculeHLA-A2. Proc. Natl. Acad. Sci. USA 98, 6794–6799.
44. Cadwell, K., Coscoy, L. (2005) Ubiquitination on nonlysine residues bya viral E3 ubiquitin ligase. Science 309, 127–130.
45. Goto, E., Ishido, S., Sato, Y., Ohgimoto, S., Ohgimoto, K., Nagano-Fujii,M., Hotta, H. (2003) c-MIR, a human E3 ubiquitin ligase, is a functionalhomolog of herpesvirus proteins MIR1 and MIR2 and has similar activ-ity. J. Biol. Chem. 278, 14657–14668.
46. Bartee, E., Mansouri, M., Hovey-Nerenberg, B. T., Gouveia, K., Fruh, K.(2004) Downregulation of major histocompatibility complex class I by
human ubiquitin ligases related to viral immune evasion proteins. J. Vi-rol. 78, 1109–1120.
47. Coscoy, L., Ganem, D. (2000) Kaposi’s sarcoma-associated herpesvirusencodes two proteins that block cell surface display of MHC class Ichains by enhancing their endocytosis. Proc. Natl. Acad. Sci. USA 9 7,8051–8056.
48. Ishido, S., Choi, J. K., Lee, B. S., Wang, C., DeMaria, M., Johnson, R. P.,Cohen, G. B., Jung, J. U. (2000) Inhibition of natural killer cell-mediatedcytotoxicity by Kaposi’s sarcoma-associated herpesvirus K5 protein. Immunity 13, 365–374.
49. Stevenson, P. G., Efstathiou, S., Doherty, P. C., Lehner, P. J. (2000)Inhibition of MHC class I-restricted antigen presentation by 2-herpes-viruses. Proc. Natl. Acad. Sci. USA 97, 8455–8460.
50. Sanchez, D. J., Gumperz, J. E., Ganem, D. (2005) Regulation of CD1dexpression and function by a herpesvirus infection. J. Clin. Invest. 115,
1369–1378.
Iannello et al. Viral immune evasion strategies 31
8/12/2019 Viral Strategies for Evading Antiviral Cellular Immune Respo
http://slidepdf.com/reader/full/viral-strategies-for-evading-antiviral-cellular-immune-respo 17/20
51. Boname, J. M., Stevenson, P. G. (2001) MHC class I ubiquitination by aviral PHD/LAP finger protein. Immunity 15, 627–636.
52. Boname, J. M., deLima, B. D., Lehner, P. J., Stevenson, P. G. (2004)Viral degradation of the MHC class I peptide loading complex. Immunity20, 305–317.
53. Wang, X., Lybarger, L., Connors, R., Harris, M. R., Hansen, T. H. (2004)Model for the interaction of herpesvirus 68 RING-CH finger proteinmK3 with major histocompatibility complex class I and the peptide-loading complex. J. Virol. 78, 8673–8686.
54. Ishido, S., Wang, C., Lee, B. S., Cohen, G. B., Jung, J. U. (2000)Downregulation of major histocompatibility complex class I molecules byKaposi’s sarcoma-associated herpesvirus K3 and K5 proteins. J. Virol.74, 5300–5309.
55. Mansouri, M., Bartee, E., Gouveia, K., Hovey-Nerenberg, B. T., Barrett,J., Thomas, L., Thomas, G., McFadden, G., Fruh, K. (2003) The PHD/LAP-domain protein M153R of myxomavirus is a ubiquitin ligase thatinduces the rapid internalization and lysosomal destruction of CD4.J. Virol. 77, 1427–1440.
56. Ahn, K., Angulo, A., Ghazal, P., Peterson, P. A., Yang, Y., Fruh, K.(1996) Human cytomegalovirus inhibits antigen presentation by a se-quential multistep process. Proc. Natl. Acad. Sci. USA 93, 10990–10995.
57. Jones, T. R., Wiertz, E. J., Sun, L., Fish, K. N., Nelson, J. A., Ploegh,H. L. (1996) Human cytomegalovirus US3 impairs transport and matu-ration of major histocompatibility complex class I heavy chains. Proc. Natl. Acad. Sci. USA 93, 11327–11333.
58. Gruhler, A., Fruh, K. (2000) Control of MHC class I traffic from theendoplasmic reticulum by cellular chaperones and viral anti-chaperones.Traffic 1, 306–311.
59. Gruhler, A., Peterson, P. A., Fruh, K. (2000) Human cytomegalovirusimmediate early glycoprotein US3 retains MHC class I molecules bytransient association. Traffic 1, 318–325.
60. Kavanagh, D. G., Gold, M. C., Wagner, M., Koszinowski, U. H., Hill,A. B. (2001) The multiple immune-evasion genes of murine cytomega-lovirus are not redundant: m4 and m152 inhibit antigen presentation ina complementary and cooperative fashion. J. Exp. Med. 194, 967–978.
61. LoPiccolo, D. M., Gold, M. C., Kavanagh, D. G., Wagner, M., Koszi-nowski, U. H., Hill, A. B. (2003) Effective inhibition of K(b)- andD(b)-restricted antigen presentation in primary macrophages by murinecytomegalovirus. J. Virol. 77, 301–308.
62. Burgert, H. G., Kvist, S. (1985) An adenovirus type 2 glycoprotein blockscell surface expression of human histocompatibility class I antigens. Cell41, 987–997.
63. Hudson, A. W., Blom, D., Howley, P. M., Ploegh, H. L. (2003) TheER-lumenal domain of the HHV-7 immunoevasin U21 directs class I
MHC molecules to lysosomes. Traffic 4, 824–837.64. Kasper, M. R., Roeth, J. F., Williams, M., Filzen, T. M., Fleis, R. I.,
Collins, K. L. (2005) HIV-1 Nef disrupts antigen presentation early in thesecretory pathway. J. Biol. Chem. 280, 12840–12848.
65. Williams, M., Roeth, J. F., Kasper, M. R., Filzen, T. M., Collins, K. L.(2005) Human immunodeficiency virus type 1 Nef domains required for disruption of major histocompatibility complex class I trafficking are alsonecessary for coprecipitation of Nef with HLA-A2. J. Virol. 79, 632–636.
66. Le Gall, S., Erdtmann, L., Benichou, S., Berlioz-Torrent, C., Liu, L.,Benarous, R., Heard, J. M., Schwartz, O. (1998) Nef interacts with the subunit of clathrin adaptor complexes and reveals a cryptic sorting signalin MHC I molecules. Immunity 8, 483–495.
67. Cohen, G. B., Gandhi, R. T., Davis, D. M., Mandelboim, O., Chen, B. K.,Strominger, J. L., Baltimore, D. (1999) The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects
HIV-infected cells from NK cells. Immunity 10, 661–671.68. Piguet, V., Wan, L., Borel, C., Mangasarian, A., Demaurex, N., Thomas,
G., Trono, D. (2000) HIV Nef protein binds to the cellular proteinPACS-1 to downregulate class I major histocompatibility complexes. Nat.Cell Biol. 2, 163–167.
69. Schwartz, O., Marechal, V., Le Gall, S., Lemonnier, F., Heard, J. M.(1996) Endocytosis of major histocompatibility complex class I mole-cules is induced by the HIV-1 Nef protein. Nat. Med. 2, 338–342.
70. Collins, K. L., Chen, B. K., Kalams, S. A., Walker, B. D., Baltimore, D.(1998) HIV-1 Nef protein protects infected primary cells against killingby cytotoxic T lymphocytes. Nature 391, 397–401.
71. Piguet, V., Schwartz, O., Le Gall, S., Trono, D. (1999) The downregula-tion of CD4 and MHC-I by primate lentiviruses: a paradigm for themodulation of cell surface receptors. Immunol. Rev. 168, 51–63.
72. Casartelli, N., Di Matteo, G., Potesta, M., Rossi, P., Doria, M. (2003) CD4and major histocompatibility complex class I downregulation by the
human immunodeficiency virus type 1 Nef protein in pediatric AIDSprogression. J. Virol. 77, 11536–11545.
73. Tolstrup, M., Ostergaard, L., Laursen, A. L., Pedersen, S. F., Duch, M.(2004) HIV/SIV escape from immune surveillance: focus on Nef. Curr. HIV Res. 2, 141–151.
74. Lorenzo, M. E., Ploegh, H. L., Tirabassi, R. S. (2001) Viral immuneevasion strategies and the underlying cell biology. Semin. Immunol. 13,
1–9.75. Momburg, F., Mullbacher, A., Lobigs, M. (2001) Modulation of trans-
porter associated with antigen processing (TAP)-mediated peptide importinto the endoplasmic reticulum by flavivirus infection. J. Virol. 75,
5663–5671.76. Herzer, K., Falk, C. S., Encke, J., Eichhorst, S. T., Ulsenheimer, A.,
Seliger, B., Krammer, P. H. (2003) Upregulation of major histocompat-ibility complex class I on liver cells by hepatitis C virus core protein viap53 and TAP1 impairs natural killer cell cytotoxicity. J. Virol. 77,8299–8309.
77. Pieters, J. (1997) MHC class II restricted antigen presentation. Curr.Opin. Immunol. 9, 89–96.
78. Wolf, P. R., Ploegh, H. L. (1995) How MHC class II molecules acquirepeptide cargo: biosynthesis and trafficking through the endocytic path-way. Annu. Rev. Cell Dev. Biol. 11, 267–306.
79. Chapman, H. A. (1998) Endosomal proteolysis and MHC class II func-tion. Curr. Opin. Immunol. 10, 93–102.
80. Bryant, P., Ploegh, H. (2004) Class II MHC peptide loading by theprofessionals. Curr. Opin. Immunol. 16, 96–102.
81. Kretsovali, A., Agalioti, T., Spilianakis, C., Tzortzakaki, E., Merika, M.,Papamatheakis, J. (1998) Involvement of CREB binding protein inexpression of major histocompatibility complex class II genes via inter-
action with the class II transactivator. Mol. Cell. Biol. 18, 6777–6783.82. Alcami, A., Koszinowski, U. H. (2000) Viral mechanisms of immuneevasion. Trends Microbiol. 8, 410–418.
83. Neumann, J., Eis-Hubinger, A. M., Koch, N. (2003) Herpes simplex virustype 1 targets the MHC class II processing pathway for immune evasion.J. Immunol. 171, 3075–3083.
84. Sievers, E., Neumann, J., Raftery, M., Schonrich, G., Eis-Hubinger,A. M., Koch, N. (2002) Glycoprotein B from strain 17 of herpes simplexvirus type I contains an invariant chain homologous sequence that bindsto MHC class II molecules. Immunology 107, 129–135.
85. Stumptner-Cuvelette, P., Morchoisne, S., Dugast, M., Le Gall, S., Raposo,G., Schwartz, O., Benaroch, P. (2001) HIV-1 Nef impairs MHC class IIantigen presentation and surface expression. Proc. Natl. Acad. Sci. USA98, 12144–12149.
86. Stumptner-Cuvelette, P., Jouve, M., Helft, J., Dugast, M., Glouzman,A. S., Jooss, K., Raposo, G., Benaroch, P. (2003) Human immunodefi-ciency virus-1 Nef expression induces intracellular accumulation of multivesicular bodies and major histocompatibility complex class IIcomplexes: potential role of phosphatidylinositol 3-kinase. Mol. Biol.Cell 14, 4857–4870.
87. Johnson, D. C., Hegde, N. R. (2002) Inhibition of the MHC class IIantigen presentation pathway by human cytomegalovirus. Curr. Top. Microbiol. Immunol. 269, 101–115.
88. Tomazin, R., Boname, J., Hegde, N. R., Lewinsohn, D. M., Altschuler,Y., Jones, T. R., Cresswell, P., Nelson, J. A., Riddell, S. R., Johnson,D. C. (1999) Cytomegalovirus US2 destroys two components of the MHCclass II pathway, preventing recognition by CD4 T cells. Nat. Med. 5,
1039–1043.89. Hegde, N. R., Tomazin, R. A., Wisner, T. W., Dunn, C., Boname, J. M.,
Lewinsohn, D. M., Johnson, D. C. (2002) Inhibition of HLA-DR assem-bly, transport, and loading by human cytomegalovirus glycoprotein US3:a novel mechanism for evading major histocompatibility complex class IIantigen presentation. J. Virol. 76, 10929–10941.
90. Ressing, M. E., van Leeuwen, D., Verreck, F. A., Gomez, R., Heemskerk,B., Toebes, M., Mullen, M. M., Jardetzky, T. S., Longnecker, R.,Schilham, M. W., Ottenhoff, T. H., Neefjes, J., Schumacher, T. N.,Hutt-Fletcher, L. M., Wiertz, E. J. (2003) Interference with T cellreceptor-HLA-DR interactions by Epstein-Barr virus gp42 results inreduced T helper cell recognition. Proc. Natl. Acad. Sci. USA 100,11583–11588.
91. Ressing, M. E., van Leeuwen, D., Verreck, F. A., Keating, S., Gomez, R.,Franken, K. L., Ottenhoff, T. H., Spriggs, M., Schumacher, T. N.,Hutt-Fletcher, L. M., Rowe, M., Wiertz, E. J. (2005) Epstein-Barr virusgp42 is posttranslationally modified to produce soluble gp42 that medi-ates HLA class II immune evasion. J. Virol. 79, 841–852.
92. Shearer, G. M. (1998) HIV-induced immunopathogenesis. Immunity 9,587–593.
93. Ishido, S., Choi, J. K., Lee, B. S., Wang, C., DeMaria, M., Johnson, R. P.,Cohen, G. B., Jung, J. U. (2000) Inhibition of natural killer cell-mediated
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cytotoxicity by Kaposi’s sarcoma-associated herpesvirus K5 protein. Immunity 13, 365–374.
94. Coscoy, L., Ganem, D. (2001) A viral protein that selectively downregu-lates ICAM-1 and B7–2 and modulates T cell costimulation. J. Clin. Invest. 107, 1599–1606.
95. Guerin, J. L., Gelfi, J., Boullier, S., Delverdier, M., Bellanger, F. A.,Bertagnoli, S., Drexler, I., Sutter, G., Messud-Petit, F. (2002) Myxomavirus leukemia-associated protein is responsible for major histocompat-ibility complex class I and Fas-CD95 down-regulation and defines scrap-ins, a new group of surface cellular receptor abductor proteins. J. Virol.76, 2912–2923.
96. Bottley, G., Cook, G. P., Meade, J. L., Holt, J. R., Hoeben, R. C., Blair,G. E. (2005) Differential expression of LFA-3, Fas and MHC class I on
Ad5- and Ad12-transformed human cells and their susceptibility tolymphokine-activated killer (LAK) cells. Virology 338, 297–308.
97. Wills, M. R., Carmichael, A. J., Mynard, K., Jin, X., Weekes, M. P.,Plachter, B., Sissons, J. G. (1996) The human cytotoxic T-lymphocyte(CTL) response to cytomegalovirus is dominated by structural proteinpp65: frequency, specificity, and T-cell receptor usage of pp65-specificCTL. J. Virol. 70, 7569–7579.
98. Reddehase, M. J., Mutter, W., Munch, K., Buhring, H. J., Koszinowski,U. H. (1987) CD8-positive T lymphocytes specific for murine cytomeg-alovirus immediate-early antigens mediate protective immunity. J. Virol.61, 3102–3108.
99. Lehner, P. J., Wilkinson, G. V. (2001) Cytomegalovirus: from evasion tosuppression? Nat. Immunol. 2, 993–994.
100. Reddehase, M. J. (2002) Antigens and immunoevasins: opponents incytomegalovirus immune surveillance. Nat. Rev. Immunol. 2, 831–844.
101. Gilbert, M. J., Riddell, S. R., Plachter, B., Greenberg, P. D. (1996)
Cytomegalovirus selectively blocks antigen processing and presentationof its immediate-early gene product. Nature 383, 720–722.
102. Arnon, T. I., Achdout, H., Levi, O., Markel, G., Saleh, N., Katz, G., Gazit,R., Gonen-Gross, T., Hanna, J., Nahari, E., Porgador, A., Honigman, A.,Plachter, B., Mevorach, D., Wolf, D. G., Mandelboim, O. (2005) Inhibi-tion of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat. Immunol. 6, 515–523.
103. Farag, S. S., Fehniger, T. A., Ruggeri, L., Velardi, A., Caligiuri, M. A.(2002) Natural killer cell receptors: new biology and insights into thegraft-versus-leukemia effect. Blood 100, 1935–1947.
104. Moretta, L., Moretta, A. (2004) Killer immunoglobulin-like receptors.Curr. Opin. Immunol. 16, 626–633.
105. Tomasec, P., Braud, V. M., Rickards, C., Powell, M. B., McSharry, B. P.,Gadola, S., Cerundolo, V., Borysiewicz, L. K., McMichael, A. J., Wilkin-son, G. W. (2000) Surface expression of HLA-E, an inhibitor of naturalkiller cells, enhanced by human cytomegalovirus gpUL40. Science 287,
1031–1033.106. Ulbrecht, M., Martinozzi, S., Grzeschik, M., Hengel, H., Ellwart, J. W.,
Pla, M., Weiss, E. H. (2000) Cutting edge: the human cytomegalovirusUL40 gene product contains a ligand for HLA-E and prevents NKcell-mediated lysis. J. Immunol. 164, 5019–5022.
107. Wang, E. C., McSharry, B., Retiere, C., Tomasec, P., Williams, S.,Borysiewicz, L. K., Braud, V. M., Wilkinson, G. W. (2002) UL40-mediated NK evasion during productive infection with human cytomeg-alovirus. Proc. Natl. Acad. Sci. USA 99, 7570–7575.
108. Braud, V. M., Tomasec, P., Wilkinson, G. W. (2002) Viral evasion of natural killer cells during human cytomegalovirus infection. Curr. Top. Microbiol. Immunol. 269, 117–129.
109. Nattermann, J., Nischalke, H. D., Hofmeister, V., Kupfer, B., Ahlenstiel,G., Feldmann, G., Rockstroh, J., Weiss, E. H., Sauerbruch, T., Spengler,U. (2005) HIV-1 infection leads to increased HLA-E expression resultingin impaired function of natural killer cells. Antivir. Ther. 10, 95–107.
110. Saverino, D., Ghiotto, F., Merlo, A., Bruno, S., Battini, L., Occhino, M.,Maffei, M., Tenca, C., Pileri, S., Baldi, L., Fabbi, M., Bachi, A., DeSantanna, A., Grossi, C. E., Ciccone, E. (2004) Specific recognition of theviral protein UL18 by CD85j/LIR-1/ILT2 on CD8 T cells mediates thenon-MHC-restricted lysis of human cytomegalovirus-infected cells.J. Immunol. 172, 5629–5637.
111. Reyburn, H. T., Mandelboim, O., Vales-Gomez, M., Davis, D. M.,Pazmany, L., Strominger, J. L. (1997) The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature386, 514–517.
112. Cosman, D., Mullberg, J., Sutherland, C. L., Chin, W., Armitage, R.,Fanslow, W., Kubin, M., Chalupny, N. J. (2001) ULBPs, novel MHCclass I-related molecules, bind to CMV glycoprotein UL16 and stimulateNK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133.
113. Sutherland, C. L., Chalupny, N. J., Schooley, K., Vanden-Bos, T., Kubin,M., Cosman, D. (2002) UL16-binding proteins, novel MHC class I-re-
lated proteins, bind to NKG2D and activate multiple signaling pathwaysin primary NK cells. J. Immunol. 168, 671–679.
114. Kubin, M., Cassiano, L., Chalupny, J., Chin, W., Cosman, D., Fanslow,W., Mullberg, J., Rousseau, A. M., Ulrich, D., Armitage, R. (2001)ULBP1, 2, 3: novel MHC class I-related molecules that bind to humancytomegalovirus glycoprotein UL16, activate NK cells. Eur. J. Immunol.31, 1428–1437.
115. Dunn, C., Chalupny, N. J., Sutherland, C. L., Dosch, S., Sivakumar,P. V., Johnson, D. C., Cosman, D. (2003) Human cytomegalovirusglycoprotein UL16 causes intracellular sequestration of NKG2D ligands,protecting against natural killer cell cytotoxicity. J. Exp. Med. 197,
1427–1439.116. Wu, J., Chalupny, N. J., Manley, T. J., Riddell, S. R., Cosman, D., Spies,
T. (2003) Intracellular retention of the MHC class I-related chain Bligand of NKG2D by the human cytomegalovirus UL16 glycoprotein.J. Immunol. 170, 4196–4200.
117. Tomasec, P., Wang, E. C., Davison, A. J., Vojtesek, B., Armstrong, M.,Griffin, C., McSharry, B. P., Morris, R. J., Llewellyn-Lacey, S., Rickards,C., Nomoto, A., Sinzger, C., Wilkinson, G. W. (2005) Downregulation of natural killer cell-activating ligand CD155 by human cytomegalovirusUL141. Nat. Immunol. 6, 181–188.
118. Hasan, M., Krmpotic, A., Ruzsics, Z., Bubic, I., Lenac, T., Halenius, A.,Loewendorf, A., Messerle, M., Hengel, H., Jonjic, S., Koszinowski, U. H.(2005) Selective down-regulation of the NKG2D ligand H60 by mousecytomegalovirus m155 glycoprotein. J. Virol. 79, 2920–2930.
119. Krmpotic, A., Hasan, M., Loewendorf, A., Saulig, T., Halenius, A.,Lenac, T., Polic, B., Bubic, I., Kriegeskorte, A., Pernjak-Pugel, E.,Messerle, M., Hengel, H., Busch, D. H., Koszinowski, U. H., Jonjic, S.(2005) NK cell activation through the NKG2D ligand MULT-1 is selec-
tively prevented by the glycoprotein encoded by mouse cytomegalovirusgene m145. J. Exp. Med. 201, 211–220.
120. Lodoen, M., Ogasawara, K., Hamerman, J. A., Arase, H., Houchins, J. P.,Mocarski, E. S., Lanier, L. L. (2003) NKG2D-mediated natural killer cellprotection against cytomegalovirus is impaired by viral gp40 modulationof retinoic acid early inducible 1 gene molecules. J. Exp. Med. 197,
1245–1253.121. Smith, H. R., Heusel, J. W., Mehta, I. K., Kim, S., Dorner, B. G.,
Naidenko, O. V., Iizuka, K., Furukawa, H., Beckman, D. L., Pingel, J. T.,Scalzo, A. A., Fremont, D. H., Yokoyama, W. M. (2002) Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl. Acad. Sci. USA 99, 8826–8831.
122. Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B., Lanier, L. L.(2002) Direct recognition of cytomegalovirus by activating and inhibitoryNK cell receptors. Science 296, 1323–1326.
123. Voigt, V., Forbes, C. A., Tonkin, J. N., Degli-Esposti, M. A., Smith,
H. R., Yokoyama, W. M., Scalzo, A. A. (2003) Murine cytomegalovirusm157 mutation and variation leads to immune evasion of natural killer cells. Proc. Natl. Acad. Sci. USA 100, 13483–13488.
124. Tseng, C. T., Klimpel, G. R. (2002) Binding of the hepatitis C virusenvelope protein E2 to CD81 inhibits natural killer cell functions. J. Exp. Med. 195, 43–49.
125. Ahmad, A., Alvarez, F. (2004) Role of NK and NKT cells in theimmunopathogenesis of HCV-induced hepatitis. J. Leukoc. Biol. 76,
743–759.126. Foy, E., Li, K., Wang, C., Sumpter Jr., R., Ikeda, M., Lemon, S. M., Gale
Jr., M. (2003) Regulation of interferon regulatory factor-3 by the hepatitisC virus serine protease. Science 300, 1145–1148.
127. Li, K., Foy, E., Ferreon, J. C., Nakamura, M., Ferreon, A. C., Ikeda, M.,Ray, S. C., Gale Jr., M., Lemon, S. M. (2005) Immune evasion byhepatitis C virus NS3/4A protease-mediated cleavage of the Toll-likereceptor 3 adaptor protein TRIF. Proc. Natl. Acad. Sci. USA 102,
2992–2997.128. Otsuka, M., Kato, N., Moriyama, M., Taniguchi, H., Wang, Y., Dharel,
N., Kawabe, T., Omata, M. (2005) Interaction between the HCV NS3protein and the host TBK1 protein leads to inhibition of cellular antiviralresponses. Hepatology 41, 1004–1012.
129. Hengel, H., Koszinowski, U. H., Conzelmann, K. K. (2005) Viruses knowit all: new insights into IFN networks. Trends Immunol. 26, 396–401.
130. Hansasuta, P., Dong, T., Thananchai, H., Weekes, M., Willberg, C.,Aldemir, H., Rowland-Jones, S., Braud, V. M. (2004) Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific. Eur. J. Immu-nol. 34, 1673–1679.
131. Browne, H., Smith, G., Beck, S., Minson, T. (1990) A complex betweenthe MHC class I homologue encoded by human cytomegalovirus and 2microglobulin. Nature 347, 770–772.
132. Fahnestock, M. L., Johnson, J. L., Feldman, R. M., Neveu, J. M., Lane,W. S., Bjorkman, P. J. (1995) The MHC class I homolog encoded by
Iannello et al. Viral immune evasion strategies 33
8/12/2019 Viral Strategies for Evading Antiviral Cellular Immune Respo
http://slidepdf.com/reader/full/viral-strategies-for-evading-antiviral-cellular-immune-respo 19/20
human cytomegalovirus binds endogenous peptides. Immunity 3, 583–590.
133. Cosman, D., Fanger, N., Borges, L., Kubin, M., Chin, W., Peterson, L.,Hsu, M. L. (1997) A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 7, 273–282.
134. Cretney, E., Degli-Esposti, M. A., Densley, E. H., Farrell, H. E., Davis-Poynter, N. J., Smyth, M. J. (1999) m144, a murine cytomegalovirus(MCMV)-encoded major histocompatibility complex class I homologue,confers tumor resistance to natural killer cell-mediated rejection. J. Exp. Med. 190, 435–444.
135. Rehermann, B., Chisari, F. V. (2000) Cell-mediated immune response tothe hepatitis C virus. Curr. Top. Microbiol. Immunol. 242, 299–325.
136. Collins, K. L. (2003) How HIV evades CTL recognition. Curr. HIV Res.
1, 31–40.137. de Campos-Lima, P. O., Levitsky, V., Brooks, J., Lee, S. P., Hu, L. F.,
Rickinson, A. B., Massuci, M. G. (1994) T cell responses and virusevolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virusisolates from highly A11-positive populations by selective mutation of anchor residues. J. Exp. Med. 179, 1297–1305.
138. Lill, N. L., Tevethia, M. J., Hendrickson, W. G., Tevethia, S. S. (1992)Cytotoxic T lymphocytes (CTL) against a transforming gene productselect for transformed cells with point mutations within sequences en-coding CTL recognition epitopes. J. Exp. Med. 176, 449–457.
139. Koup, R. A. (1994) Virus escape from CTL recognition. J. Exp. Med.180, 779–782.
140. Reid, A. H., Taubenberger, J. K., Fanning, T. G. (2004) Evidence of anabsence: the genetic origins of the 1918 pandemic influenza virus. Nat. Rev. Microbiol. 2, 909–914.
141. Tsurumi, T., Fujita, M., Kudoh, A. (2005) Latent and lytic Epstein-Barr
virus replication strategies. Rev. Med. Virol. 15, 3–15.142. Khanna, K. M., Lepisto, A. J., Decman, V., Hendricks, R. L. (2004)Immune control of herpes simplex virus during latency. Curr. Opin. Immunol. 16, 463–469.
143. Saksena, N. K., Potter, S. J. (2003) Reservoirs of HIV-1 in vivo: impli-cations for antiretroviral therapy. AIDS Rev. 5, 3–18.
144. Collins, K. L. (2004) Resistance of HIV-infected cells to cytotoxic Tlymphocytes. Microbes Infect. 6, 494–500.
145. Champagne, P., Ogg, G. S., King, A. S., Knabenhans, C., Ellefsen, K.,Nobile, M., Appay, V., Rizzardi, G. P., Fleury, S., Lipp, M., Forster, R.,Rowland-Jones, S., Sekaly, R. P., McMichael, A. J., Pantaleo, G. (2001)Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature410, 106–111.
146. Papagno, L., Spina, C. A., Marchant, A., Salio, M., Rufer, N., Little, S.,Dong, T., Chesney, G., Waters, A., Easterbrook, P., Dunbar, P. R.,Shepherd, D., Cerundolo, V., Emery, V., Griffiths, P., Conlon, C., Mc-Michael, A. J., Richman, D. D., Rowland-Jones, S. L., Appay, V. (2004)Immune activation and CD8 T-cell differentiation towards senescencein HIV-1 infection. PLoS Biol. 2, E20.
147. Appay, V., Nixon, D. F., Donahoe, S. M., Gillespie, G. M., Dong, T.,King, A., Ogg, G. S., Spiegel, H. M., Conlon, C., Spina, C. A., Havlir,D. V., Richman, D. D., Waters, A., Easterbrook, P., McMichael, A. J.,Rowland-Jones, S. L. (2000) HIV-specific CD8() T cells produceantiviral cytokines but are impaired in cytolytic function. J. Exp. Med.192, 63–75.
148. Vidalain, P. O., Azocar, O., Lamouille, B., Astier, A., Rabourdin-Combe,C., Servet-Delprat, C. (2000) Measles virus induces functional TRAILproduction by human dendritic cells. J. Virol. 74, 556–559.
149. Muller, D. B., Raftery, M. J., Kather, A., Giese, T., Schonrich, G. (2004)Frontline: induction of apoptosis and modulation of c-FLIPL and p53 inimmature dendritic cells infected with herpes simplex virus. Eur. J. Im-munol. 34, 941–951.
150. James, C. O., Huang, M. B., Khan, M., Garcia-Barrio, M., Powell, M. D.,
Bond, V. C. (2004) Extracellular Nef protein targets CD4 T cells for apoptosis by interacting with CXCR4 surface receptors. J. Virol. 78,3099–3109.
151. Majumder, B., Janket, M. L., Schafer, E. A., Schaubert, K., Huang, X. L.,Kan-Mitchell, J., Rinaldo Jr., C. R., Ayyavoo, V. (2005) Human immu-nodeficiency virus type 1 Vpr impairs dendritic cell maturation andT-cell activation: implications for viral immune escape. J. Virol. 79,
7990–8003.152. Shi, Y. (2002) Mechanisms of caspase activation and inhibition during
apoptosis. Mol. Cell 9, 459–470.153. Benedict, C. A., Norris, P. S., Ware, C. F. (2002) To kill or be killed:
viral evasion of apoptosis. Nat. Immunol. 3, 1013–1018.154. Miyazato, A., Sheleg, S., Iha, H., Li, Y., Jeang, K. T. (2005) Evidence for
NF-B- and CBP-independent repression of p53’s transcriptional activ-ity by human T-cell leukemia virus type 1 Tax in mouse embryo andprimary human fibroblasts. J. Virol. 79, 9346–9350.
155. Liu, M. T., Chang, Y. T., Chen, S. C., Chuang, Y. C., Chen, Y. R., Lin,C. S., Chen, J. Y. (2005) Epstein-Barr virus latent membrane protein 1represses p53-mediated DNA repair and transcriptional activity. Onco- gene 24, 2635–2646.
156. Green, N. K., Seymoor, L. W. (2002) Adenoviral vectors: systemicdelivery and tumor targeting. Cancer Gene Ther. 9, 1036–1042.
157. Goldmacher, V. S., Bartle, L. M., Skaletskaya, A., Dionne, C. A.,Kedersha, N. L., Vater, C. A., Han, J. W., Lutz, R. J., Watanabe, S.,Cahir-McFarland, E. D., Kieff, E. ., Mocarski, E. S., Chittenden, T.(1999) A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc. Natl. Acad. Sci. USA 96,
12536–12541.158. Munger, J., Chee, A. V., Roizman, B. (2001) The U(S)3 protein kinase
blocks apoptosis induced by the d120 mutant of herpes simplex virus 1at a pre-mitochondrial stage. J. Virol. 75, 5491–5497.
159. Thome, M., Tschopp, J. (2001) Regulation of lymphocyte proliferationand death by FLIP. Nat. Rev. Immunol. 1, 50–58.
160. Wang, G. H., Bertin, J., Wang, Y., Martin, D. A., Wang, J., Tomaselli,K. J., Armstrong, R. C., Cohen, J. I. (1997) Bovine herpesvirus 4BORFE2 protein inhibits Fas- and tumor necrosis factor receptor 1-in-duced apoptosis and contains death effector domains shared with other -2 herpesviruses. J. Virol. 71, 8928–8932.
161. Bertin, J., Armstrong, R. C., Ottilie, S., Martin, D. A., Wang, Y., Banks,S., Wang, G. H., Senkevich, T. G., Alnemri, E. S., Moss, B., Lenardo,M. J., Tomaselli, K. J., Cohen, J. I. (1997) Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- andTNFR1-induced apoptosis. Proc. Natl. Acad. Sci. USA 94, 1172–1176.
162. Meinl, E., Fickenscher, H., Thome, M., Tschopp, J., Fleckenstein, B.(1998) Anti-apoptotic strategies of lymphotropic viruses. Immunol. To-
day 19, 474–479.163. Skaletskaya, A., Bartle, L. M., Chittenden, T., McCormick, A. L., Mo-carski, E. S., Goldmacher, V. S. (2001) A cytomegalovirus-encodedinhibitor of apoptosis that suppresses caspase-8 activation. Proc. Natl. Acad. Sci. USA 98, 7829–7834.
164. Chaudhary, P. M., Jasmin, A., Eby, M. T., Hood, L. (1999) Modulation of the NF- B pathway by virally encoded death effector domain-containingproteins. Oncogene 18, 5738–5746.
165. Hay, B. A. (2000) Understanding IAP function and regulation: a viewfrom Drosophila. Cell Death Differ. 7, 1045–1056.
166. Deveraux, Q. L., Reed, J. C. (1999) IAP family proteins—suppressors of apoptosis. Genes Dev. 13, 239–252.
167. Beidler, D. R., Tewari, M., Friesen, P. D., Poirier, G., Dixit, V. M. (1995)The baculovirus p35 protein inhibits Fas- and tumor necrosis factor-induced apoptosis. J. Biol. Chem. 270, 16526–16528.
168. Jerome, K. R., Chen, Z., Lang, R., Torres, M. R., Hofmeister, J., Smith,S., Fox, R., Froelich, C. J., Corey, L. (2001) HSV and glycoprotein Jinhibit caspase activation and apoptosis induced by granzyme B or Fas.J. Immunol. 167, 3928–3935.
169. Nash, P., Barrett, J., Cao, J. X., Hota-Mitchell, S., Lalani, A. S., Everett,H., Xu, X. M., Robichaud, J., Hnatiuk, S., Ainslie, C., Seet, B. T.,McFadden, G. (1999) Immunomodulation by viruses: the myxoma virusstory. Immunol. Rev. 168, 103–120.
170. Tewari, M., Dixit, V. M. (1995) Fas- and tumor necrosis factor-inducedapoptosis is inhibited by the poxvirus CrmA gene product. J. Biol. Chem.270, 3255–3260.
171. Tewari, M., Telford, W. G., Miller, R. A., Dixit, V. M. (1995) CrmA, apoxvirus-encoded serpin, inhibits cytotoxic T-lymphocyte-mediatedapoptosis. J. Biol. Chem. 270, 22705–22708.
172. Talley, A. K., Dewhurst, S., Perry, S. W., Dollard, S. C., Gummuluru, S.,Fine, S. M., New, D., Epstein, L. G., Gendelman, H. E., Gelbard, H. A.(1995) Tumor necrosis factor -induced apoptosis in human neuronalcells: protection by the antioxidant N-acetylcysteine and the genes bcl-2
and CrmA. Mol. Cell. Biol. 15, 2359–2366.173. Miura, M., Friedlander, R. M., Yuan, J. (1995) Tumor necrosis factor-
induced apoptosis is mediated by a CrmA-sensitive cell death pathway. Proc. Natl. Acad. Sci. USA 92, 8318–8322.
174. Geleziunas, R., Xu, W., Takeda, K., Ichijo, H., Greene, W. C. (2001)HIV-1 Nef inhibits ASK1-dependent death signaling providing a poten-tial mechanism for protecting the infected host cell. Nature 410, 834–838.
175. Sedger, L. M., Shows, D. M., Blanton, R. A., Peschon, J. J., Goodwin,R. G., Cosman, D., Wiley, S. R. (1999) IFN- mediates a novel antiviralactivity through dynamic modulation of TRAIL and TRAIL receptor expression. J. Immunol. 163, 920–926.
176. Raftery, M. J., Schwab, M., Eibert, S. M., Samstag, Y., Walczak, H.,Schonrich, G. (2001) Targeting the function of mature dendritic cells byhuman cytomegalovirus: a multilayered viral defense strategy. Immunity15, 997–1009.
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177. Raftery, M. J., Behrens, C. K., Muller, A., Krammer, P. H., Walczak, H.,Schonrich, G. (1999) Herpes simplex virus type 1 infection of activatedcytotoxic T cells: induction of fratricide as a mechanism of viral immuneevasion. J. Exp. Med. 190, 1103–1114.
178. Windheim, M., Hilgendorf, A., Burgert, H. G. (2004) Immune evasion byadenovirus E3 proteins: exploitation of intracellular trafficking pathways.Curr. Top. Microbiol. Immunol. 273, 29–85.
179. Tollefson, A. E., Hermiston, T. W., Lichtenstein, D. L., Colle, C. F.,Tripp, R. A., Dimitrov, T., Toth, K., Wells, C. E., Doherty, P. C., Wold,W. S. (1998) Forced degradation of Fas inhibits apoptosis in adenovirus-infected cells. Nature 392, 726–730.
180. Shisler, J., Yang, C., Walter, B., Ware, C. F., Gooding, L. R. (1997) Theadenovirus E3–10.4K/14.5K complex mediates loss of cell surface Fas
(CD95) and resistance to Fas-induced apoptosis. J. Virol. 71, 8299–8306.
181. Stewart, A. R., Tollefson, A. E., Krajcsi, P., Yei, S. P., Wold, W. S.(1995) The adenovirus E3 10.4K and 14.5K proteins, which function toprevent cytolysis by tumor necrosis factor and to down-regulate theepidermal growth factor receptor, are localized in the plasma membrane.J. Virol. 69, 172–181.
182. Ashkenazi, A., Dixit, V. M. (1999) Apoptosis control by death and decoyreceptors. Curr. Opin. Cell Biol. 11, 255–260.
183. Xu, X. N., Screaton, G. R., Gotch, F. M., Dong, T., Tan, R., Almond, N.,Walker, B., Stebbings, R., Kent, K., Nagata, S., Stott, J. E., McMichael,A. J. (1997) Evasion of cytotoxic T lymphocyte (CTL) responses byNef-dependent induction of Fas ligand (CD95L) expression on simianimmunodeficiency virus-infected cells. J. Exp. Med. 186, 7–16.
184. Quaranta, M. G., Mattioli, B., Giordani, L., Viora, M. (2004) HIV-1 Nef equips dendritic cells to reduce survival and function of CD8 T cells:
a mechanism of immune evasion. FASEB J. 18, 1459–1461.185. Zhang, M., Li, X., Pang, X., Ding, L., Wood, O., Clouse, K., Hewlett, I.,
Dayton, A. I. (2001) Identification of a potential HIV-induced source of bystander-mediated apoptosis in T cells: upregulation of TRAIL inprimary human macrophages by HIV-1 Tat. J. Biomed. Sci. 8, 290–296.
186. Li, C. J., Friedman, D. J., Wang, C., Metelev, V., Pardee, A. B. (1995)Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein.Science 268, 429–431.
187. Bartz, S. R., Emerman, M. (1999) Human immunodeficiency virus type 1Tat induces apoptosis and increases sensitivity to apoptotic signals byup-regulating FLICE/caspase-8. J. Virol. 73, 1956–1963.
188. Westendorp, M. O., Frank, R., Ochsenbauer, C., Stricker, K., Dhein, J.,Walczak, H., Debatin, K. M., Krammer, P. H. (1995) Sensitization of Tcells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375,
497–500.189. Casella, C. R., Rapaport, E. L., Finkel, T. H. (1999) Vpu increases
susceptibility of human immunodeficiency virus type 1-infected cells tofas killing. J. Virol. 73, 92–100.
190. Onuffer, J. J., Horuk, R. (2002) Chemokines, chemokine receptors andsmall-molecule antagonists: recent developments. Trends Pharmacol.Sci. 23, 459–467.
191. Alcami, A. (2003) Viral mimicry of cytokines, chemokines and their receptors. Nat. Rev. Immunol. 3, 36–50.
192. Hsu, D. H., de Waal-Malefyt, R., Fiorentino, D. F., Dang, M. N., Vieira,P., de Vries, J., Spits, H., Mosmann, T. R., Moore, K. W. (1990)Expression of interleukin-10 activity by Epstein-Barr virus proteinBCRF1. Science 250, 830–832.
193. Kotenko, S. V., Saccani, S., Izotova, L. S., Mirochnitchenko, O. V.,Pestka, S. (2000) Human cytomegalovirus harbors its own unique IL-10homolog (cmvIL-10). Proc. Natl. Acad. Sci. USA 97, 1695–1700.
194. Spencer, J. V., Lockridge, K. M., Barry, P. A., Lin, G., Tsang, M.,Penfold, M. E., Schall, T. J. (2002) Potent immunosuppressive activitiesof cytomegalovirus-encoded interleukin-10. J. Virol. 76, 1285–1292.
195. Jones, B. C., Logsdon, N. J., Josephson, K., Cook, J., Barry, P. A., Walter,M. R. (2002) Crystal structure of human cytomegalovirus IL-10 bound tosoluble human IL-10R1. Proc. Natl. Acad. Sci. USA 99, 9404–9409.
196. Bartlett, N. W., Dumoutier, L., Renauld, J. C., Kotenko, S. V., McVey,C. E., Lee, H. J., Smith, G. L. (2004) A new member of the interleukin10-related cytokine family encoded by a poxvirus. J. Gen. Virol. 85,1401–1412.
197. Tripp, R. A., Jones, L. P., Haynes, L. M., Zheng, H., Murphy, P. M.,Anderson, L. J. (2001) CX3C chemokine mimicry by respiratory syncy-tial virus G glycoprotein. Nat. Immunol. 2, 732–738.
198. Loparev, V. N., Parsons, J. M., Knight, J. C., Panus, J. F., Ray, C. A.,Buller, R. M., Pickup, D. J., Esposito, J. J. (1998) A third distinct tumor necrosis factor receptor of orthopoxviruses. Proc. Natl. Acad. Sci. USA95, 3786–3791.
199. Smith, V. P., Bryant, N. A., Alcami, A. (2000) Ectromelia, vaccinia andcowpox viruses encode secreted interleukin-18-binding proteins. J. Gen.Virol. 81, 1223–1230.
200. van Berkel, V., Levine, B., Kapadia, S. B., Goldman, J. E., Speck, S. H.,Virgin IV, H. W. (2002) Critical role for a high-affinity chemokine-binding protein in gamma-herpesvirus-induced lethal meningitis. J. Clin. Invest. 109, 905–914.
201. Howard, A. D., Palyha, O. C., Griffin, P. R., Peterson, E. P., Lenny, A. B.,Ding, G. J., Pickup, D. J., Thornberry, N. A., Schmidt, J. A., Tocci, M. J.(1995) Human IL-1 processing and secretion in recombinant baculo-virus-infected Sf9 cells is blocked by the cowpox virus serpin CrmA.J. Immunol. 154, 2321–2332.
202. Armour, K. L., Atherton, A., Williamson, L. M., Clark, M. R. (2002) Thecontrasting IgG-binding interactions of human and herpes simplex virusFc receptors. Biochem. Soc. Trans. 30, 495–500.
203. Lilley, B. N., Ploegh, H. L., Tirabassi, R. S. (2001) Human cytomegalo-virus open reading frame TRL11/IRL11 encodes an immunoglobulin GFc-binding protein. J. Virol. 75, 11218–11221.
204. Proft, T., Fraser, J. D. (2003) Bacterial superantigens. Clin. Exp. Immu-nol. 133, 299–306.
205. Conrad, B., Weissmahr, R. N., Boni, J., Arcari, R., Schupbach, J., Mach,B. (1997) A human endogenous retroviral superantigen as candidateautoimmune gene in type 1 diabetes. Cell 90, 303–313.
206. Woodland, D. L. (2002) Immunity and retroviral superantigens in hu-mans. Trends Immunol. 23, 57–58.
207. Sutkowski, N., Conrad, B., Thorley-Lawson, D. A., Hubert, B. T. (2001)
Epstein-Barr virus transactivates the human endogenous retrovirusHERV-K18 that encodes a superantigen. Immunity 15, 579–589.
208. Stauffer, Y., Marguerat, S., Meylan, F., Ucla, C., Sutkowski, N., Hubert,B., Pelet, T., Conrad, B. (2001) Interferon--induced endogenous super-antigen: a model linking environment and autoimmunity. Immunity 15,591–601.
209. Ardavin, C., Martin, P., Ferrero, I., Azcoitia, I., Anjuere, F., Diggelmann,H., Luthi, F., Luther, S., Acha-Orbea, H. (1999) B cell response after MMTV infection: extrafollicular plasmablasts represent the main in-fected population and can transmit viral infection. J. Immunol. 162,2538–2545.