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.
Highlights
Herpesviruses are distinguished by their ability to establish lifelong infection cycling between lytic and latent phases
Depletion of CD4 T cells did not abolish the increase in viral load in the spinal cord of 27US11- or 27m152-infected BALB/c, as compared to 27gfpinfected mice (Figure S1). These findings indicate that HSVspecific CD8 T cells are controlling 27gfp, but not 27US11 or 27m152, and are consistent with the notion that the increased neurovirulence and neuroinvasiveness of 27US11 and 27m152 recombinant herpes simplex virus (rHSV) are attributable to major histocompatibility complex (MHC) class I inhibition and evasion of CD8 T cells
We show that two different rHSVs, 27US11 and 27m152, efficiently inhibited antigen presentation by MHC class I molecules on murine cells, as does wild-type Herpes simplex virus (HSV) on human cells
Summary
Herpesviruses are distinguished by their ability to establish lifelong infection cycling between lytic and latent phases One challenge to this lifestyle is that the immune system of the vertebrate hosts has the opportunity to be repeatedly primed, thereby increasing the potential for the host to eradicate the pathogen. To cope with this challenge, herpesviruses have evolved multiple mechanisms to evade immune detection or clearance. The murine cytomegalovirus (MCMV) m152 gene product gp binds to the MHC class I/ peptide complex in the ER/cis-Golgi compartment preventing export to the cell surface [6,7]. MCMV m152 inhibits expression of ligands for the activating NK cell receptor NKG2D, while MCMV m157 binds to members of the Ly49 family of NK cell receptors, which include both inhibitory and activating receptors [11,12,13]
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