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Coordinated Function of Murine Cytomegalovirus Genes Completely Inhibits CTL Lysis¹

Amelia K. Pinto^*, Michael W. Munks^*, Ulrich H. Koszinowski and Ann B. Hill^2,*

^* Oregon Health and Science University, Molecular Microbiology and Immunology, Portland, OR 97239; and Ludwig Maximilians University of Munich, Max von Pettenkofer Institute, Munich, Germany

Murine CMV (MCMV) encodes three viral genes that interfere with Ag presentation (VIPRs) to CD8 T cells, m04, m06, and m152. Because the functional impact of these genes during normal infection of C57BL/6 mice is surprisingly modest, we wanted to determine whether the VIPRs are equally effective against the entire spectrum of H-2^b-restricted CD8 T cell epitopes. We also wanted to understand how the VIPRs interact at a functional level. To address these questions, we used a panel of MCMV mutants lacking each VIPR in all possible combinations, and CTL specific for 15 H-2^b-restricted MCMV epitopes. Only expression of all three MCMV VIPRs completely inhibited killing by CTL specific for all 15 epitopes, but removal of any one VIPR enabled lysis by at least some CTL. The dominant interaction between the VIPRs was cooperation: m06 increased the inhibition of lysis achieved by either m152 or m04. However, for 1 of 15 epitopes m04 functionally antagonized m152. There was little differential impact of any of the VIPRs on K^b vs D^b, but a surprising degree of differential impact of the three VIPRs for different epitopes. These epitope-specific differences did not correlate with functional avidity, or with timing of VIPR expression in relation to Ag expression in the virus replication cycle. Although questions remain about the molecular mechanism and in vivo role of these genes, we conclude that the coordinated function of MCMV’s three VIPRs results in a powerful inhibition of lysis of infected cells by CD8 T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was support by National Institutes of Health (AI47206A and AI50099A; to A.B.H.), American Heart Association Fellowship (0215188Z; to A.K.P.), National Eye Institute training grant (ACAEI0071; to A.K.P.), and Deutsche Forschungsgemeinschaft (SFB 455; to U.H.K.).

² Address correspondence and reprint requests to Dr. Ann B. Hill, Oregon Health Science University, Department of Microbiology and Immunology, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239; E-mail address: hillan{at}ohsu.edu

³ Abbreviations used in this paper used in this paper: MCMV, murine CMV; ER, endoplasmic reticulum; ERGIC, ER-Golgi intermediate compartment; HCMV, human CMV; BAC, bacterial artificial chromosome; BMM, primary bone marrow macrophage; wt, wild type; MOI, multiplicity of infection; PAA, phosphonoacetic acid; RT, reverse transcriptase; MFI, mean fluorescence intensity; IE, immediately early.

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