Hsp90 inhibitors suppress HCV replication in replicon cells and humanized liver mice.
Persistent infection with hepatitis C virus (HCV) is a major cause of liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Here we report that inhibition of heat shock protein 90 (Hsp90) is highly effective in suppressing HCV genome replication. In HCV replicon cells, HCV replication was reduced by Hsp90 inhibitors and by knockdown of endogenous Hsp90 expression mediated by small-interfering RNA (siRNA). The suppression of HCV replication by an Hsp90 inhibitor was prevented by transfection with Hsp90 expression vector. We also tested the anti-HCV effect of Hsp90 inhibition in HCV-infected chimeric mice with humanized liver. Combined administration of an Hsp90 inhibitor and polyethylene glycol-conjugated interferon (PEG-IFN) was more effective in reducing HCV genome RNA levels in serum than was PEG-IFN monotherapy. These results suggest that inhibition of Hsp90 could provide a new therapeutic approach to HCV infection.
Nakagawa
Shin-ichiro
S
Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
Umehara
Takuya
T
Matsuda
Chiho
C
Kuge
Shusuke
S
Sudoh
Masayuki
M
Kohara
Michinori
M
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000254:growth & development; D006526:Hepatitis C / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects* / Q000637:transplantation / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D011092:Polyethylene Glycols / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D011994:Recombinant Proteins; D012093:Replicon / Q000187:drug effects; D017828:Rifabutin / Q000031:analogs & derivatives; D013997:Time Factors; D014162:Transfection; D018183:Transplantation Chimera / Q000821:virology; D014183:Transplantation, Heterologous; D014779:Virus Replication / Q000187:drug effects*
D016227:Benzoquinones; D006360:Heat-Shock Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047029:Lactams, Macrocyclic; D018942:Macrolides; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011994:Recombinant Proteins; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D017828:Rifabutin; D011092:Polyethylene Glycols; C020754:herbimycin; C035359:monorden; C100416:peginterferon alfa-2a; C001277:geldanamycin