Inhibition of MHC Class I Is a Virulence Factor in Herpes Simplex Virus Infection of Mice

PLoS Pathogens

Mark T Orr¹  Kurt H Edelmann¹  David H Raulet²  Jeffrey Vieira²  Lawrence Corey³  Christopher B Wilson³ 

[1] Department of Immunology, University of Washington, Seattle, Washington, United States of America;Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America;Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

关键词: Major histocompatibility complex;    Cytotoxic T cells;    MHC class I genes;    Antigen presentation;    T cells;    Mouse models;    Central nervous system;    NK cells;   

DOI  :  10.1371/journal.ppat.0010007

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Herpes simplex virus (HSV) has a number of genes devoted to immune evasion. One such gene, ICP47, binds to the transporter associated with antigen presentation (TAP) 1/2 thereby preventing transport of viral peptides into the endoplasmic reticulum, loading of peptides onto nascent major histocompatibility complex (MHC) class I molecules, and presentation of peptides to CD8 T cells. However, ICP47 binds poorly to murine TAP1/2 and so inhibits antigen presentation by MHC class I in mice much less efficiently than in humans, limiting the utility of murine models to address the importance of MHC class I inhibition in HSV immunopathogenesis. To address this limitation, we generated recombinant HSVs that efficiently inhibit antigen presentation by murine MHC class I. These recombinant viruses prevented cytotoxic T lymphocyte killing of infected cells in vitro, replicated to higher titers in the central nervous system, and induced paralysis more frequently than control HSV. This increase in virulence was due to inhibition of antigen presentation to CD8 T cells, since these differences were not evident in MHC class I-deficient mice or in mice in which CD8 T cells were depleted. Inhibition of MHC class I by the recombinant viruses did not impair the induction of the HSV-specific CD8 T-cell response, indicating that cross-presentation is the principal mechanism by which HSV-specific CD8 T cells are induced. This inhibition in turn facilitates greater viral entry, replication, and/or survival in the central nervous system, leading to an increased incidence of paralysis.

【 授权许可】

CC BY