Chapter 31 : Viral Immune Evasion

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Viral Immune Evasion, Page 1 of 2

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This chapter focuses on the study of viral immune evasion. Most viruses spread from one host to the next via secreted bodily fluids; to gain access to their target cells for replication they need to cross epithelial barriers, which can be considered the first line of host defense. Host cell apoptosis is triggered by cell stress signals responding to the virus' attempt to co-opt cellular machinery. Pattern recognition receptors (PRRs) recognize viral components and elicit cytokines and chemokines, which in turn recruit natural killer (NK) cells. Natural killer (NK) cells are an essential component of the first line of defense against viruses. NK cells have two antiviral mechanisms, cytotoxicity and cytokine secretion, and they are the main source of INF-g early in infection. Viral genes that interfere with the MHCI pathway of antigen presentation to CD8 T cells were the first viral immune evasion genes to be described. Specific deletion of viral immune evasion genes has revealed the extraordinary potency of innate immune responses compared to the modest impact of the sophisticated adaptive immune system. However, all viral immune evasion genes, whether they are absolutely required for host species infection or confer a barely perceptible benefit, have been selected by the same balancing evolutionary pressures: the ability of a virus to propagate its genome within a host, the ability to spread to a new host, and the need to maintain a supply of new hosts.

Citation: Farrington L, O’Neill G, Hill A. 2011. Viral Immune Evasion, p 393-401. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch31
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The apoptotic pathway and its inhibition by viruses. The intrinsic cell death pathway is initiated when internal sensors (for example p53) activate BH3-domain only members of the Bcl-2 family. These sensors are inactivated by viral p53 inhibitors like adenovirus E1B-55K. BH3-domain-only proteins mediate assembly of pro-apoptotic Bcl-2 family members (for example Bid, Bax, Bok) into pores in the outer mitochondrial membrane, actions that are antagonized by Bcl-2 orthologs produced by viruses like adenovirus, KSHV, EBV, and HCMV. Cytochrome c and other factors are released into the cytoplasm, promoting formation of a complex containing Apaf-I and pro-caspase 9 called the apoptosome. Caspase-9 is activated, triggering executioner caspases 2, 3, 6, and 7. vIAPs (encoded by baculoviruses and African swine fever virus) as well as many non-BIR containing viral proteins such as p35 (baculoviruses) and the serpin CrmA (poxviruses) inhibit caspases. The extrinsic cell death pathway is initiated by TNF-family death receptors (e.g., FAS, TRAIL, TNFR) binding to their cognate ligand and facilitating the binding of adaptor proteins to pro-caspase-8 and/or 10 to form the DISC. Inactive caspases (pro-caspases) are cleaved to their active forms, triggering caspase-3 and initiating the mitochondrial cell death pathway via activation of Bid. Herpesviruses and orthopox viruses produce soluble decoy receptors to block death-receptor signaling. The adenovirus E3 protein targets TNF-family receptors for degradation. The HCMV protein vICA inhibits pro-caspase 8 activation and vFLIPs prevent the formation of the DISC complex.

Citation: Farrington L, O’Neill G, Hill A. 2011. Viral Immune Evasion, p 393-401. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch31
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Mechanisms of viral inhibition of NK cells. Viruses have developed a variety of mechanisms to oppose NK function including: (i) direct effects on NK cells by the virus, (ii) expression of viral MHC class I-homologs, (iii) modulation of MHC class I molecules by viral proteins, (iv) inhibition of NK cell activation, and (v) interference with NK cell cytokine/chemokine pathways. HCV envelope protein E2 binds and cross-links NK cell surface protein CD81 resulting in inhibition of NK cell cytotoxicity, proliferation, and IFN-γ production. HCMV encodes UL18, an MHC class I homolog, which is able to inhibit NK cells via inhibitory receptor ILT2. HIV selectively down modulates HLA-A and HLA-B but not HLA-C or HLA-E via viral protein MCMV prevents NK cell stimulation by decreasing cell surfaces levels of RAE-1, MULT1, and H60, NKG2D receptor ligands in mice, via viral proteins m152, m145 and m155, respectively. HCMV also down modulates MICB and MICA, human ligands for NKG2D, via UL16, UL142, and miRNA miR-UL112. Finally, KSHV encodes for a broad chemokine antagonist, vMIP-II, which binds CC and CXC chemokine receptors and prevents immune cell chemotaxis.

Citation: Farrington L, O’Neill G, Hill A. 2011. Viral Immune Evasion, p 393-401. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch31
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Mechanisms of viral inhibition of the MHC class I antigen presentation pathway. Proteins in the cytosol are degraded by the proteasome, transported into the ER by TAP, and loaded onto MHCI, which then traffics to the cell surface as indicated by dashed arrows. Many viruses inhibit the TAP transporter by a variety of methods, from both cytosolic and lumenal sides. HCMV , Ad5E3/19K, CPXV203, and MCMVml52 retain MHCI in pre-Golgi compartments. HCMV and target MHCI for retrotranslocation and proteasomal degradation. MCMV directs MHCI to the lysosome for degradation. HIV reduces MHCI at the plasma membrane by a complex set of reactions. KSHV and MHV-68 K3 and K5 proteins ubiquitinate the cytosolic tail of MHCI and target it to the lysosome. This list is not exhaustive: MHCI synthesis is also targeted, and other new mechanisms are being discovered all the time.

Citation: Farrington L, O’Neill G, Hill A. 2011. Viral Immune Evasion, p 393-401. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch31
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1. Alzhanova,, D.,, D. M. Edwards,, E. Hammarlund,, I. G. Scholz,, D. Horst,, M. J. Wagner,, C. Upton,, E. J. Wiertz,, M. K. Slifka, and, K. Fruh. 2009. Cowpox virus inhibits the transporter associated with antigen processing to evade T cell recognition. Cell Host Microbe. 6:433445.
2. Benedict, C. A.,, P. S. Norris, and, C. F. Ware. 2002. To kill or be killed: viral evasion of apoptosis. Nat. Immunol. 3:10131018.
3. Bennett, N. J.,, J. S. May, and, P. G. Stevenson. 2005. Gammaherpesvirus latency requires T cell evasion during episome maintenance. PLoS Biol. 3:e120.
4. Best, S. M. 2008. Viral subversion of apoptotic enzymes: escape from death row. Annu. Rev. Microbiol. 62:171192.
5. Chinsangaram, J.,, M. E. Piccone, and, M. J. Grubman. 1999. Ability of foot-and-mouth disease virus to form plaques in cell culture is associated with suppression of alpha/beta interferon. J. Virol. 73:98919898.
6. Collins,, K. L.,, B. K. Chen,, S. A. Kalams,, B. D. Walker, and, D. Baltimore. 1998. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391:397401.
7. Croft,, N. P.,, C. Shannon-Lowe,, A. I. Bell,, D. Horst,, E. Kremmer,, M. E. Ressing,, E. J. Wiertz,, J. M. Middeldorp,, M. Rowe,, A. B. Rickinson, and, A. D. Hislop. 2009. Stage-specific inhibition of MHC class I presentation by the Epstein-Barr virus BNLF2a protein during virus lytic cycle. PLoS Pathog. 5:e1000490.
8. Doom, C. M., and, A. B. Hill. 2008. MHC class I immune evasion in MCMV infection. Med. Microbiol. Immunol. 197:191204.
9. Goldmacher,, V. S.,, L. M. Bartle,, A. Skaletskaya,, C. A. Dionne,, N. L. Kedersha,, C. A. Vater,, J. W. Han,, R. J. Lutz,, S. Watanabe,, E. D. Cahir McFarland,, E. D. Kieff,, E. S. Mocarski, and, T. Chittenden. 1999. A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc. Natl. Acad. Sci. USA 96:1253612541.
10. Gorman,, S.,, N. L. Harvey,, D. Moro,, M. L. Lloyd,, V. Voigt,, L. M. Smith,, M. A. Lawson, and, G. R. Shellam. 2006. Mixed infection with multiple strains of murine cytomegalovirus occurs following simultaneous or sequential infection of immunocompetent mice. J. Gen. Virol. 87:11231132.
11. Goulder, P. J., and, D. I. Watkins. 2004. HIV and SIV CTL escape: implications for vaccine design. Nat. Rev. Immunol. 4:630640.
12. Hammarlund, E.,, A. Dasgupta,, C. Pinilla,, P. Norori,, K. Fruh, and, M. K. Slifka. 2008. Monkeypox virus evades antiviral CD4+ and CD8+ T cell responses by suppressing cognate T cell activation. Proc. Natl. Acad. Sci. USA 105:1456714572.
13. Hansen, T. H., and, M. Bouvier. 2009. MHC class I antigen presentation: learning from viral evasion strategies. Nat. Rev. Immunol. 9:503513.
14. Hedrick, S. M. 2004. The acquired immune system: a vantage from beneath. Immunity 21:607615.
15. Holtappels, R.,, J. Podlech,, M. F. Pahl-Seibert,, M. Julch,, D. Thomas,, C. O. Simon,, M. Wagner, and, M. J. Reddehase. 2004. Cytomegalovirus misleads its host by priming of CD8 T cells specific for an epitope not presented in infected tissues. J. Exp. Med. 199:131136.
16. Jonjic, S.,, M. Babic,, B. Polic, and, A. Krmpotic. 2008. Immune evasion of natural killer cells by viruses. Curr. Opin. Immunol. 20:3038.
17. Jurak, I., and, W. Brune. 2006. Induction of apoptosis limits cytomegalovirus cross-species infection. EMBO J. 25:26342642.
18. Kledal,, T. N.,, M. M. Rosenkilde,, F. Coulin,, G. Simmons,, A. H. Johnsen,, S. Alouani,, C. A. Power,, H. R. Luttichau,, J. Gerstoft,, P. R. Clapham,, I. Clark-Lewis,, T. N. Wells, and, T. W. Schwartz. 1997. A broad-spectrum chemokine antagonist encoded by Kaposi’s sarcoma-associated herpesvirus. Science. 277:16561659.
19. Lane, D. P., and, L. V. Crawford. 1979. T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261263.
20. Langland,, J. O.,, J. M. Cameron,, M. C. Heck,, J. K. Jancovich, and, B. L. Jacobs. 2006. Inhibition of PKR by RNA and DNA viruses. Virus Res. 119:100110.
21. Lu,, X.,, A. K. Pinto,, A. M. Kelly,, K. S. Cho, and, A. B. Hill. 2006. Murine cytomegalovirus interference with antigen presentation contributes to the inability of CD8 T cells to control virus in the salivary gland. J. Virol. 80:42004202.
22. Malim, M. H. 2006. Natural resistance to HIV infection: the Vif-APOBEC interaction. Comptes Rendus Biol. 329:871875.
23. McFadden, G.,, M. R. Mohamed,, M. M. Rahman, and, E. Bartee. 2009. Cytokine determinants of viral tropism. Nat. Rev. Immunol. 9:645655.
24. Munch, J.,, N. Stolte,, D. Fuchs,, C. Stahl-Hennig, and, F. Kirchhoff. 2001. Efficient class I major histocompatibility complex down-regulation by simian immunodeficiency virus Nef is associated with a strong selective advantage in infected rhesus macaques. J. Virol. 75:1053210536.
25. Munger, J., and, B. Roizman. 2001. The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc. Natl. Acad. Sci. USA 98:1041010415.
26. Munks,, M. W.,, A. K. Pinto,, C. M. Doom, and, A. B. Hill. 2007. Viral interference with antigen presentation does not alter acute or chronic CD8 T cell immunodominance in murine cytomegalovirus infection. J. Immunol. 178:72357241.
27. Nachmani, D.,, N. Stern-Ginossar,, R. Sarid, and, O. Mandelboim. 2009. Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe. 5:376385.
28. Orange,, J. S.,, M. S. Fassett,, L. A. Koopman,, J. E. Boyson, and, J. L. Strominger. 2002. Viral evasion of natural killer cells. Nat. Immunol. 3:10061012.
29. Paabo, S.,, B. M. Bhat,, W. S. Wold, and, P. A. Peterson. 1987. A short sequence in the COOH-terminus makes an adenovirus membrane glycoprotein a resident of the endoplasmic reticulum. Cell 50:311317.
30. Pinto, A. K., and, A. B. Hill. 2005. Viral interference with antigen presentation to CD8+ T cells: lessons from cytomegalovirus. Viral Immunol. 18:434444.
31. Powers, C.,, V. DeFilippis,, D. Malouli, and, K. Fruh. 2008. Cytomegalovirus immune evasion. Curr. Top. Microbiol. Immunol. 325:333359.
32. Pyzik, M.,, A. Kielczewska, and, S. M. Vidal. 2008. NK cell receptors and their MHC class I ligands in host response to cytomegalovirus: insights from the mouse genome. Semin. Immunol. 20:331342.
33. Raftery,, M. J.,, M. Schwab,, S. M. Eibert,, Y. Samstag,, H. Walczak, and, G. Schonrich. 2001. Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy. Immunity 15:9971009.
34. Randall, R. E., and, S. Goodbourn. 2008. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol. 89:147.
35. Skaletskaya,, A.,, L. M. Bartle,, T. Chittenden,, A. L. McCormick,, E. S. Mocarski, and, V. S. Goldmacher. 2001. A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation. Proc. Natl. Acad. Sci. USA 98:78297834.
36. Smith,, C. A.,, T. Davis,, D. Anderson,, L. Solam,, M. P. Beckmann,, R. Jerzy,, S. K. Dower,, D. Cosman, and, R. G. Goodwin. 1990. A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science. 248:10191023.
37. Stanford, M. M., and, G. McFadden. 2007. Myxoma virus and oncolytic virotherapy: a new biologic weapon in the war against cancer. Expert Opin. Biol. Ther. 7:14151425.
38. Steegenga,, W. T.,, N. Riteco,, A. G. Jochemsen,, F. J. Fallaux, and, J. L. Bos. 1998. The large E1B protein together with the E4orf6 protein target p53 for active degradation in adenovirus infected cells. Oncogene 16:349357.
39. Stevenson,, P. G. 2004. Immune evasion by gamma-herpesviruses. Curr. Opin. Immunol. 16:456462.
40. Stevenson, P. G.,, S. Efstathiou,, P. C. Doherty, and, P. J. Lehner. 2000. Inhibition of MHC class I-restricted antigen presentation by gamma 2-herpesviruses. Proc. Natl. Acad. Sci. USA 97:84558460.
41. Wang, F.,, Y. Ma,, J. W. Barrett,, X. Gao,, J. Loh,, E. Barton,, H. W. Virgin, and, G. McFadden. 2004. Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier. Nat. Immunol. 5:12661274.
42. Wang,, X. W.,, M. K. Gibson,, W. Vermeulen,, H. Yeh,, K. Forrester,, H. W. Sturzbecher,, J. H. Hoeijmakers, and, C. C. Harris. 1995. Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Res. 55:60126016.
43. Werden, S. J.,, M. M. Rahman, and, G. McFadden. 2008. Poxvirus host range genes. Adv. Virus Res. 71:135171.
44. White, E.,, R. Cipriani,, P. Sabbatini, and, A. Denton. 1991. Adenovirus E1B 19-kilodalton protein overcomes the cytotoxicity of E1A proteins. J. Virol. 65:29682978.
45. Wolf, D.,, V. Witte,, B. Laffert,, K. Blume,, E. Stromer,, S. Trapp,, P. d’Aloja,, A. Schurmann, and, A. S. Baur. 2001. HIV-1 Nef associated PAK and PI3-kinases stimulate Aktindependent Bad-phosphorylation to induce antiapoptotic signals. Nat. Med. 7:12171224.

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