title: Critical role of virion-associated cholesterol and sphingolipid in hepatitis C virus infection.
abstract: In this study, we establish that cholesterol and sphingolipid associated with hepatitis C virus (HCV) particles are important for virion maturation and infectivity. In a recently developed culture system enabling study of the complete life cycle of HCV, mature virions were enriched with cholesterol as assessed by the molar ratio of cholesterol to phospholipid in virion and cell membranes. Depletion of cholesterol from the virus or hydrolysis of virion-associated sphingomyelin almost completely abolished HCV infectivity. Supplementation of cholesterol-depleted virus with exogenous cholesterol enhanced infectivity to a level equivalent to that of the untreated control. Cholesterol-depleted or sphingomyelin-hydrolyzed virus had markedly defective internalization, but no influence on cell attachment was observed. Significant portions of HCV structural proteins partitioned into cellular detergent-resistant, lipid-raft-like membranes. Combined with the observation that inhibitors of the sphingolipid biosynthetic pathway block virion production, but not RNA accumulation, in a JFH-1 isolate, our findings suggest that alteration of the lipid composition of HCV particles might be a useful approach in the design of anti-HCV therapy.
authors: Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
authors: Hideki
authors: H
authors: Aizaki
authors: Kenichi
authors: K
authors: Morikawa
authors: Masayoshi
authors: M
authors: Fukasawa
authors: Hiromichi
authors: H
authors: Hara
authors: Yasushi
authors: Y
authors: Inoue
authors: Hideki
authors: H
authors: Tani
authors: Kyoko
authors: K
authors: Saito
authors: Masahiro
authors: M
authors: Nishijima
authors: Kentaro
authors: K
authors: Hanada
authors: Yoshiharu
authors: Y
authors: Matsuura
authors: Michael M C
authors: MM
authors: Lai
authors: Tatsuo
authors: T
authors: Miyamura
authors: Takaji
authors: T
authors: Wakita
authors: Tetsuro
authors: T
authors: Suzuki
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism*; D006526:Hepatitis C / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008113:Liver Neoplasms / Q000473:pathology; D021962:Membrane Microdomains / Q000502:physiology; D010957:Plasmids; D013107:Sphingolipids / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology; D014771:Virion / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D013107:Sphingolipids; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol; D013108:Sphingomyelin Phosphodiesterase