Regulation of hepatitis C virus replication by interferon regulatory factor 1.
Cellular antiviral responses are mediated partly by the expression of interferon-stimulated genes, triggered by viral genomes, their transcripts and replicative intermediates. Persistent replication of a hepatitis C virus (HCV) replicon suggests that the replicon does not elicit cellular innate antiviral responses. In the present study, we investigated regulatory factors of the interferon-mediated antiviral system in cells expressing an HCV replicon. Luciferase reporter assays revealed that the baseline activity of the interferon-stimulated response element (ISRE) was significantly lower in cells harboring the replicon than in naive cells. Among the proteins involved in the IFN/Jak/STAT pathway and in ISRE activity, the expression level of interferon regulatory factor 1 (IRF-1) was found to be significantly lower in cells harboring the replicon. Transfection of an IRF-1 expression construct into cells harboring the replicon caused an increase of ISRE activity, accompanied by suppression of expression of the HCV replicon. Moreover, in cured Huh7 cells from which the HCV replicon had been eliminated, the expression levels of IRF-1 and ISRE activity also were suppressed, demonstrating that the decrease of IRF-1 is attributable, not to active suppression by the viral proteins, but to adaptation of cells that enables replication of the HCV subgenome. The high permissiveness of the cured cells for the replicon was abolished by transgenic supplementation of IRF-1 expression. Taken together, IRF-1 is one of the key host factors that regulate intracellular HCV replication through modulation of interferon-stimulated-gene-mediated antiviral responses.
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Nobuhiko
N
Kanazawa
Masayuki
M
Kurosaki
Naoya
N
Sakamoto
Nobuyuki
N
Enomoto
Yasuhiro
Y
Itsui
Tsuyoshi
T
Yamashiro
Yoko
Y
Tanabe
Shinya
S
Maekawa
Mina
M
Nakagawa
Cheng-Hsin
CH
Chen
Sei
S
Kakinuma
Shigeru
S
Oshima
Tetsuya
T
Nakamura
Takanobu
T
Kato
Takaji
T
Wakita
Mamoru
M
Watanabe
D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007372:Interferons / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D012093:Replicon; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D007372:Interferons