Us3 kinase encoded by herpes simplex virus 1 mediates downregulation of cell surface major histocompatibility complex class I and evasion of CD8+ T cells.
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.
Division of Molecular Virology, Department of Microbiology and Immunology, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan.
Takahiko
T
Imai
Naoto
N
Koyanagi
Ryo
R
Ogawa
Keiko
K
Shindo
Tadahiro
T
Suenaga
Ayuko
A
Sato
Jun
J
Arii
Akihisa
A
Kato
Hiroshi
H
Kiyono
Hisashi
H
Arase
Yasushi
Y
Kawaguchi
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D005260:Female; D023061:Gene Order; D016679:Genome, Viral; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
D000956:Antigens, Viral; D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1