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Abstract
Detection and elimination of virus-infected cells by CD8+ cytotoxic T lymphocytes (CTLs) depends on recognition of virus-derived peptides presented by major histocompatibility complex class I (MHC-I) molecules on the surface of infected cells. In the present study, we showed that inactivation of the activity of viral kinase Us3 encoded by herpes simplex virus 1 (HSV-1), the etiologic agent of several human diseases and a member of the alphaherpesvirinae, significantly increased cell surface expression of MHC-I, thereby augmenting CTL recognition of infected cells in vitro. Overexpression of Us3 by itself had no effect on cell surface expression of MHC-I and Us3 was not able to phosphorylate MHC-I in vitro, suggesting that Us3 indirectly downregulated cell surface expression of MHC-I in infected cells. We also showed that inactivation of Us3 kinase activity induced significantly more HSV-1-specific CD8+ T cells in mice. Interestingly, depletion of CD8+ T cells in mice significantly increased replication of a recombinant virus encoding a kinase-dead mutant of Us3, but had no effect on replication of a recombinant virus in which the kinase-dead mutation was repaired. These results indicated that Us3 kinase activity is required for efficient downregulation of cell surface expression of MHC-I and mediates evasion of HSV-1-specific CD8+ T cells. Our results also raised the possibility that evasion of HSV-1-specific CD8+ T cells by HSV-1 Us3-mediated inhibition of MHC-I antigen presentation might in part contribute to viral replication in vivo.
Highlights
Herpes simplex virus-1 (HSV-1) is the member of the Alphaherpesvirinae, the neurotropic subfamily of herpesviruses [1]
We previously reported that HSV-1 Us3 directly phosphorylates HSV-1 envelope glycoprotein B and downregulates its cell surface expression in infected cells by promoting gB endocytosis [30,31]
Us3 homologs in varicella zoster virus (VZV) and pseudorabies virus (PRV) down-regulate cell surface expression of major histocompatibility complex class I (MHC-I) in infected cells, as described above [20] and reported by Deruelle [21]. These observations prompted us to examine whether MHC-I is a target of HSV-1 Us3 in the regulation of its cell surface expression in infected cells
Summary
Herpes simplex virus-1 (HSV-1) is the member of the Alphaherpesvirinae, the neurotropic subfamily of herpesviruses [1]. HSV-1 causes a life-long infection cycling between lytic and latent phases in the natural human host [1]. This HSV-1 life-cycle repeatedly primes the host immune system, thereby increasing the potential for the host to eradicate the virus. To overcome this situation, HSV-1 has had to evolve mechanisms to evade immune detection and clearance [2,3]. The MHC-I antigen presentation pathway seems to be a prime target for herpesviruses to attack to evade the host immune system. The data that these in vitro mechanisms affect viral replication and pathogenesis in vivo is limited to some non-human, animal herpesviruses in the Betaherpesvirinae or
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