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8/12/2019 Viral Strategies for Evading Antiviral Cellular Immune Respo
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.
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
8/12/2019 Viral Strategies for Evading Antiviral Cellular Immune Respo
D. ILT family:ILT 1–10 HLA-A, -B, -C, -G A or ICoreceptors:
1. CD11a/C18 (LFA-1) CD54 (ICAM-1) A, Cos, Con2. CD2 (LFA-2) CD58 (LFA-3) CD48 A, Cos, Con3. CD8 MHC class I Cos4. CD69 ? Cos5. CD56 Self Homotypic adhesion6. CD16 (FcRIIa) Fc regions of IgG, IgE A7. CD244 (2B4) CD48, CD2 (weakly) A or I8. NTB-A ? A or I9. NKR-P1 Ocil A or I
10. DNAM-1 CD155, CD112 Cos
HCMV, Human cytomegalovirus; MICA/B, MHC class I heavy chain-like protein A/B; ULBP1-4, UL-16-binding protein 1–4; Lys, lysine; Asn, asparagine;
LFA-1, lymphocyte function antigen-1; ICAM-1, intercellular adhesion molecule-1; FcRIIa, Fc receptor for IgGIIa; NTB-A, NK-T and -B cell antigen; NKR-P1,
NK cell receptor protein 1; Ocil, osteoclast inhibitory lectin; DNAM-1, DNAX accessory molecule 1. The letters denote: A, Activation; Cos, costimulation; I,
inhibition; Con, conjugate formation with target cells. * The LY 49 genes represent functional homologues of KIR in mice.
18 Journal of Leukocyte Biology Volume 79, January 2006 http://www.jleukbio.org
8/12/2019 Viral Strategies for Evading Antiviral Cellular Immune Respo
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.
22 Journal of Leukocyte Biology Volume 79, January 2006 http://www.jleukbio.org
8/12/2019 Viral Strategies for Evading Antiviral Cellular Immune Respo
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
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
28 Journal of Leukocyte Biology Volume 79, January 2006 http://www.jleukbio.org
8/12/2019 Viral Strategies for Evading Antiviral Cellular Immune Respo
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.
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:
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
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
32 Journal of Leukocyte Biology Volume 79, January 2006 http://www.jleukbio.org
8/12/2019 Viral Strategies for Evading Antiviral Cellular Immune Respo
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.
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
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.