Val193 and Phe195 of the gamma 1 34.5 protein of herpes simplex virus 1 are required for viral resistance to interferon-alpha/beta.
Herpes simplex viruses (HSV) are resistant to the antiviral action of interferon. However, the underlying mechanisms are not well understood. In this report, we show that unlike that of wild-type HSV-1, replication of the gamma 1 34.5 null mutants was significantly inhibited by exogenous interferon-alpha in cells devoid of interferon-alpha/beta genes. Using a series of gamma 1 34.5 deletion mutants, the domain required for interferon resistance was mapped to the region containing amino acids 146 to 263 in the gamma 1 34.5 protein. Interestingly, Val193 Glu and Phe195 Leu substitutions in the protein phosphatase 1 interacting motif of the gamma 1 34.5 protein rendered HSV-1 sensitive to interferon-alpha. Furthermore, gamma 1 34.5 null mutants were sensitive to interferon-alpha/beta in PKR+/+ but not in PKR-/- mouse embryo fibroblasts. These findings provide evidence that the gamma 1 34.5 protein contributes to HSV-1 resistance to interferon-alpha/beta by inhibiting PKR function.
Cheng
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G
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA.
Brett
M E
ME
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B
B
D000596:Amino Acids; D000818:Animals; D001665:Binding Sites; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral; D005347:Fibroblasts / Q000166:cytology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D016899:Interferon-beta / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010649:Phenylalanine / Q000235:genetics / Q000502:physiology; D014633:Valine / Q000235:genetics / Q000502:physiology; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication; D019892:eIF-2 Kinase
D000596:Amino Acids; D016898:Interferon-alpha; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; D010649:Phenylalanine; D016899:Interferon-beta; D019892:eIF-2 Kinase; D014633:Valine