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Chapter 31 : Viral Immune Evasion

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Viral Immune Evasion, Page 1 of 2

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Abstract:

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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FIGURE 1

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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Image of FIGURE 2
FIGURE 2

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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Image of FIGURE 3
FIGURE 3

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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