Induction of suppressor of cytokine signaling-3 by herpes simplex virus type 1 confers efficient viral replication.
We showed previously that infection of herpes simplex virus type 1 (HSV-1) rapidly induced the suppressor of cytokine signaling-3 (SOCS3), a host negative regulator of the JAK/STAT pathway, in the amnion cell line FL. Thus, HSV-1 suppresses the interferon (IFN) signaling pathway at the step of IFN-induced phosphorylation of janus kinases during an early infection stage. In the present study, we examined SOCS3 induction by HSV-1 infection in several types of human cell lines. FL cells and the T-cell line CCRF-CEM strongly induced SOCS3 during HSV-1 infection. The virus rapidly propagated in both cell lines and produced a lytic infection. On the other hand, the monocytic cell lines U937 and THP-1, and the B-cell line AKATA showed neither SOCS3 induction nor suppression of IFN-induced STAT1 phosphorylation during HSV-1 infection. These cell lines resulted in a persistent or prolonged infection, which continuously produced a low titer of infectious virus. The induction of SOCS3 by HSV-1 should occur via STAT3 activation immediately after HSV-1 infection. SOCS3 induction was inhibited by the addition of a Jak3 inhibitor WHI-P131. Treatment with WHI-P131 or transfection of antisense oligonucleotides specific for SOCS3 dramatically suppressed replication of HSV-1 in FL cells. The suppression of viral replication by WHI-P131 was released in the presence of neutralizing anti-IFN-alpha and anti-IFN-beta antibodies. In conclusion, suppression of IFN signaling by HSV-1-induced SOCS3 is required for efficient replication and lytic infection of HSV-1. The SOCS3 induction varied among cell lines, indicating that it is an important factor determining the cell type specificity of efficient HSV-1 replication.
Yokota
Shin-ichi
S
Department of Microbiology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556 Hokkaido, Japan.
Yokosawa
Noriko
N
Okabayashi
Tamaki
T
Suzutani
Tatsuo
T
Fujii
Nobuhiro
N
D000650:Amnion / Q000821:virology; D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D053616:Janus Kinase 3; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000821:virology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D020298:U937 Cells; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D011799:Quinazolines; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C116180:WHI P131; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3