Us3 kinase encoded by herpes simplex virus 1 mediates downregulation of cell surface major histocompatibility complex class I and evasion of CD8+ T cells
- PMID: 23951282
- PMCID: PMC3741198
- DOI: 10.1371/journal.pone.0072050
Us3 kinase encoded by herpes simplex virus 1 mediates downregulation of cell surface major histocompatibility complex class I and evasion of CD8+ T cells
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.
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References
-
- Roizman B, Knipe DM, Whitley RJ (2007) Herpes Simplex Viruses. In: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA. Fields Virology. 5th ed. Philadelphia, P.A.: Lippincott-Williams & Wilkins.
-
- Hansen TH, Bouvier M (2009) MHC class I antigen presentation: learning from viral evasion strategies. Nat Rev Immunol 9: 503-513. doi:10.1038/nri2575. PubMed: 19498380. - DOI - PubMed
-
- Horst D, Verweij MC, Davison AJ, Ressing ME, Wiertz EJ (2011) Viral evasion of T cell immunity: ancient mechanisms offering new applications. Curr Opin Immunol 23: 96-103. doi:10.1016/j.coi.2010.11.005. PubMed: 21146386. - DOI - PubMed
-
- Stevenson PG, May JS, Smith XG, Marques S, Adler H et al. (2002) K3-mediated evasion of CD8(+) T cells aids amplification of a latent gamma-herpesvirus. Nat Immunol 3: 733-740. doi:10.1038/nrg922. PubMed: 12101398. - DOI - PubMed
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