Murine cytomegalovirus m157 mutation and variation leads to immune evasion of natural killer cells

Voigt, Valentina; Forbes, Catherine A.; Tonkin, Joanne; Degli-Esposti, Mariapia A.; Smith, Hamish R.C.; Yokoyama, Wayne M.; Scalzo, Anthony A.

doi:10.1073/pnas.2233572100

Cited by 176 publications

(189 citation statements)

References 41 publications

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“…These results are consistent with previous studies of EBV suggesting that gammaherpesviruses can mutate immunodominant viral epitopes in response to host immune pressure. In vivo mutation of a betaherpesvirus in response to immune selection has previously been shown for murine cytomegalovirus (MCMV) recognized by Ly49H-expressing natural killer (NK) cells (9,26). The data presented here show that a similar phenomenon can occur for a gammaherpesvirus under CD8 T cell-mediated immune pressure.…”

supporting

confidence: 70%

Specific Mutation of a Gammaherpesvirus-Expressed Antigen in Response to CD8 T Cell SelectionIn Vivo

Loh

Popkin

Droit

et al. 2012

J Virol

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Herpesviruses are thought to be highly genetically stable, and their use as vaccine vectors has been proposed. However, studies of the human gammaherpesvirus, Epstein-Barr virus, have found viral isolates containing mutations in HLA class I-restricted epitopes. Using murine gammaherpesvirus 68 expressing ovalbumin (OVA), we examined the stability of a gammaherpesvirus antigenic locus under strong CD8 T cell selection in vivo. OVA-specific CD8 T cells selected viral isolates containing mutations in the OVA locus but minimal alterations in other genomic regions. Thus, a CD8 T cell response to a gammaherpesvirusexpressed antigen that is not essential for replication or pathogenesis can result in selective mutation of that antigen in vivo. This finding may have relevance for the use of herpesvirus vectors for chronic antigen expression in vivo.V iruses utilize diverse mechanisms for escaping the host immune response. Many RNA viruses can rapidly alter immunogenic viral antigens, whereas large double-stranded DNA (dsDNA) viruses, such as herpesviruses, are thought to rely on subversion and evasion instead. Factors that contribute to this difference include the longer replication cycle for herpesviruses, greater fidelity of DNA-dependent DNA polymerases, and the ability of herpesviruses to encode immunomodulatory molecules in their large genomes. Herpesviruses can also establish latent infections during which virus-infected cells are less effectively recognized by the host immune response. These strategies facilitate establishment of the lifelong persistence in hosts that is a characteristic of herpesvirus infection. Thus, herpesviruses are believed to remain genetically stable in spite of a strong host adaptive immune response. Because the use of herpesviruses in vaccine protocols as a means of expressing heterologous antigens from persistent viral vectors has been previously proposed (11,12), the stability of herpesvirus genomes under immune pressure is an important consideration.There is evidence for mutation of immunodominant herpesvirus epitopes in response to immune pressure. A bone marrow transplant patient with Epstein-Barr virus (EBV)-associated lymphoproliferative disease who was treated with adoptively transferred EBV-specific cytotoxic T lymphocytes (CTLs) developed progressive disease and died. Tumor cells from this patient were found to be resistant to cytolysis by the EBV-specific CTLs, and sequence analysis revealed a mutation that deleted the two immunodominant epitopes recognized by the CTLs (10). Studies have also examined EBV sequence variations in human populations with differing prevalences of specific human leukocyte antigen (HLA) alleles. EBV isolates from populations with a high frequency of the HLA A11 allele were found to contain mutations in an immunodominant A11-restricted viral epitope (7,8,18). These mutations abrogate both peptide binding to the A11 molecule and CTL recognition of lymphoblastoid cell lines (LCL) carrying these EBV mutants. Although these data are consistent with the hyp...

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supporting

confidence: 70%

Specific Mutation of a Gammaherpesvirus-Expressed Antigen in Response to CD8 T Cell SelectionIn Vivo

Loh

Popkin

Droit

et al. 2012

J Virol

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“…As previously reported [31][32][33], structure of virus such as mouse cytomegalovirus (MCMV) m157 may be recognized as the ligand of activating or inhibitory NK cell receptor (so called ''none-self''), by which NK cells may attack self-tissue. Until now, no report including our preliminary study (data not shown) demonstrates that HBsAg has the character.…”

Section: Discussionmentioning

confidence: 98%

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Chen

Sun

Jiang

et al. 2007

Journal of Hepatology

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Background/Aims: The role of natural killer (NK) cells in the development of hepatitis B virus (HBV)-associated liver injury remains obscure. In this study, we elucidated the role of NK cells in liver injury of HBsAg transgenic mice (HBs-B6), a mimic of human healthy chronic HBsAg carriers, triggered by polyinosinic:polycytidylic acid [Poly(I:C)].Methods: HBs-B6 or wild B6 mice were intraperitoneally injected with Poly(I:C) at different doses. Liver injury was evaluated by serum transaminase activity and histopathologic changes.Results: HBs-B6 mice were over-sensitive to Poly(I:C)-induced liver injury, which was absolutely dependent on the presence of NK cells and IFN-c produced by intrahepatic NK cells. Much stronger IFN-c receptor expression was observed on hepatocytes of HBs-B6 mice, which was significantly enhanced by Poly(I:C) injection. Treatment with IFN-c in vitro triggered much higher activation of downstream signals (pSTAT1-IRF-1) in hepatocytes of HBs-B6 mice. Depletion of Kupffer cells and neutralization of endogenous IL-12 did not affect Poly(I:C)-induced over-sensitive liver injury in HBs-B6 mice.Conclusions: NK cells played a critical role in an IFN-c dependent, Kupffer cell-and IL-12-independent manner in oversensitive liver injury triggered by Poly(I:C) in murine chronic HBsAg carriers. Ó

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“…Recent studies have indicated that certain mutations in the m157 gene resulted in immune evasion of MCMV from the NK cells of infected B6 mice, which are normally resistant to such a virus (26,27). This escape ability is largely attributed to the failure of mutant m157 to engage Ly49H-activating receptors.…”

Section: Discussionmentioning

confidence: 99%

Structural elucidation of the m157 mouse cytomegalovirus ligand for Ly49 natural killer cell receptors

Adams¹,

Juo

Venook

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells express activating and inhibitory receptors that, in concert, survey cells for proper expression of cell surface major histocompatibility complex (MHC) class I molecules. The mouse cytomegalovirus encodes an MHC-like protein, m157, which is the only known viral antigen to date capable of engaging both activating (Ly49H) and inhibitory (Ly49I) NK cell receptors. We have determined the 3D structure of m157 and studied its biochemical and cellular interactions with the Ly49H and Ly49I receptors. m157 has a characteristic MHC-fold, yet possesses several unique structural features not found in other MHC class I-like molecules. m157 does not bind peptides or other small ligands, nor does it associate with ␤2-microglobulin. Instead, m157 engages in extensive intraand intermolecular interactions within and between its domains to generate a compact minimal MHC-like molecule. m157's binding affinity for Ly49I (K d Ϸ 0.2 M) is significantly higher than that of classical inhibitory Ly49 -MHC interactions. Analysis of viral escape mutations on m157 that render it resistant to NK killing reveals that it is likely to be recognized by Ly49H in a binding mode that differs from Ly49/MHC-I. In addition, Ly49H؉ NK cells can efficiently lyse RMA cells expressing m157, despite the presence of native MHC class I. Collectively, our results show that m157 represents a structurally divergent form of MHC class I-like proteins that directly engage Ly49 receptors with appreciable affinity in a noncanonical fashion.immune system ͉ molecular recognition M ouse strains differ in their susceptibility to infection by mouse cytomegalovirus (MCMV), and protection is mediated by natural killer (NK) cells (1). NK cell-mediated resistance to MCMV infection was mapped to a genetic locus on mouse chromosome 6 in a region named the ''natural killer gene complex'' (1). This region encodes both inhibitory and activating lectin-like Ly49 receptors that, in concert, regulate NK cell activity through recognition of major histocompatibility complex (MHC) class I ligands. In C57BL/6 mice, the receptor encoded by the Ly49H gene (Ly49H) is responsible for controlling MCMV replication in visceral organs (2-4). BALB/c mice do not possess a Ly49H gene, and consequently they restrict MCMV replication; however, transgenic expression of a genomic Ly49H gene in these mice confers resistance to MCMV replication (5). Subsequent studies demonstrated that Ly49H specifically recognizes the m157 glycoprotein encoded by MCMV (6, 7). m157 is expressed on the surface of MCMV-infected cells and anchored through a phosphatidylinositol glycan linker (6,8). In addition to Ly49H, m157 also binds to at least one inhibitory receptor, Ly49I 129/J , expressed in the MCMV-susceptible mouse strain 129/J (6). Structural prediction indicated that m157 is structurally similar to that of an MHC class I molecule (6, 7), despite lacking appreciable sequence similarity.Class I MHC proteins are membrane-bound heterodimeric proteins consisting of a polymorphic heavy chain...

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Murine cytomegalovirus m157 mutation and variation leads to immune evasion of natural killer cells

Cited by 176 publications

References 41 publications

Specific Mutation of a Gammaherpesvirus-Expressed Antigen in Response to CD8 T Cell SelectionIn Vivo

Specific Mutation of a Gammaherpesvirus-Expressed Antigen in Response to CD8 T Cell SelectionIn Vivo

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Structural elucidation of the m157 mouse cytomegalovirus ligand for Ly49 natural killer cell receptors

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