Targeting lipid metabolism in the treatment of hepatitis C virus infection.
Recently, microdomains of organelle membranes rich in sphingomyelin and cholesterol (called "lipid rafts") have been considered to act as a scaffold for the hepatitis C virus (HCV) replication complex. Using the HCV cell culture system, we investigated the effect of myriocin, a sphingomyelin synthesis inhibitor, on HCV replication. We also investigated the combined effect of myriocin with interferon (IFN) and myriocin with simvastatin. Myriocin suppressed replication of both a genotype 1b subgenomic HCV replicon (Huh7/Rep-Feo) and genotype 2a infectious HCV (JFH-1 HCV) in a dose-dependent manner (for subgenomic HCV-1b, maximum of 79% at 1000 nmol/L; for genomic HCV-2a, maximum of 40% at 1000 nmol/L). Combination treatment with myriocin and IFN or myriocin and simvastatin attenuated HCV RNA replication synergistically in Huh7/Rep-Feo cells. Our data demonstrate that the sphingomyelin synthesis inhibitor strongly suppresses replication of both the subgenomic HCV-1b replicon and the JFH-1 strain of genotype 2a infectious HCV, indicating that lipid metabolism could be a novel target for HCV therapy.
Amemiya
Fumitake
F
First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Chuo, Japan.
Maekawa
Shinya
S
Itakura
Yoshie
Y
Kanayama
Asuka
A
Matsui
Akira
A
Takano
Shinichi
S
Yamaguchi
Tatsuya
T
Itakura
Jun
J
Kitamura
Takatoshi
T
Inoue
Taisuke
T
Sakamoto
Minoru
M
Yamauchi
Kozue
K
Okada
Shunichi
S
Yamashita
Atsuya
A
Sakamoto
Naoya
N
Itoh
Masahiko
M
Enomoto
Nobuyuki
N
D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D006526:Hepatitis C / Q000628:therapy*; D006801:Humans; D008055:Lipids / Q000502:physiology*; D008113:Liver Neoplasms; D010957:Plasmids; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D008055:Lipids; D034741:RNA, Small Interfering; C012491:phytosphingosine; D013110:Sphingosine