Inhibition of MHC class I-restricted antigen presentation by γ2-herpesviruses

Inhibition of MHC class I-restricted antigen presentation by γ2-herpesviruses

^*Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom; ^§Division of Immunology, Department of Pathology, The Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Addenbrookes Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom; and ^‡Department of Immunology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105

Contributed by Peter C. Doherty

Abstract

The γ-herpesviruses, in contrast to the α- and β-herpesviruses, are not known to inhibit antigen presentation to CD8⁺ cytotoxic T lymphocytes (CTLs) during lytic cycle replication. However, murine γ-herpesvirus 68 causes a chronic lytic infection in CD4⁺ T cell-deficient mice despite the persistence of a substantial CTL response, suggesting that CTL evasion occurs. Here we show that, distinct from host protein synthesis shutoff, γ-herpesvirus 68 down-regulates surface MHC class I expression on lytically infected fibroblasts and inhibits their recognition by antigen-specific CTLs. The viral K3 gene, encoding a zinc-finger-containing protein, dramatically reduced the half-life of nascent class I molecules and the level of surface MHC class I expression and was by itself sufficient to block antigen presentation. The homologous K3 and K5 genes of the related Kaposi's sarcoma-associated virus also inhibited antigen presentation and decreased cell surface expression of HLA class I antigens. Thus it appears that an immune evasion strategy shared by at least two γ-herpesviruses allows continued lytic infection in the face of strong CTL immunity.

Footnotes

↵ † To whom reprint requests should be addressed at: Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK. E-mail: pgs27{at}mole.bio.cam.ac.uk.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.150240097.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.150240097
Abbreviations:

CTL,

CD8+ cytotoxic T lymphocytes;

γHV-68,

murine γ-herpesvirus 68;

GFP,

green fluorescent protein;

KSHV,

Kaposi's sarcoma-associated herpesvirus;

MEF,

murine embryonic fibroblast;

pfu,

plaque-forming units