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

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Abstract
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. While animal models are often instructive in understanding human diseases, many factors that influence disease differ between mouse and man. Although mice can be experimentally infected with HSV-1, this virus has evolved as a human pathogen. One facet of this evolution is HSV's mechanisms to evade the immune response, allowing the virus to persist for the lifetime of the human host. This evasion includes preventing CD8 T cells from recognizing and killing infected cells by inhibiting the expression of the molecule that presents viral peptides to CD8 T cells: major histocompatibility complex (MHC) class I. HSV is unable to inhibit mouse MHC class I, thus rendering this immune-evasion strategy inoperative in the mouse. To better understand the biology of HSV infection and the immune response to this virus in humans, the authors corrected this deficiency by inserting a gene which inhibits murine MHC class I. This recombinant virus demonstrates that MHC class I inhibition is an important determinant of disease progression. The authors found that the recombinant HSV still effectively elicits a CD8 T-cell response, but this response is ineffective in controlling the infection. This finding reveals the important distinction between the size of the immune response and the effectiveness of the response, which may be important to HSV vaccine studies.