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Journal of Virology, June 2008, p. 5715-5724, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02530-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Critical Role of Virion-Associated Cholesterol and Sphingolipid in Hepatitis C Virus Infection{triangledown}

Hideki Aizaki,1 Kenichi Morikawa,1 Masayoshi Fukasawa,2 Hiromichi Hara,1 Yasushi Inoue,1 Hideki Tani,3 Kyoko Saito,2 Masahiro Nishijima,2 Kentaro Hanada,2 Yoshiharu Matsuura,3 Michael M. C. Lai,4 Tatsuo Miyamura,1 Takaji Wakita,1 and Tetsuro Suzuki1*

Department of Virology II,1 Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640,2 Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan,3 Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California 90033-10544

Received 27 November 2007/ Accepted 17 March 2008

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.

* Corresponding author. Mailing address: Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. Phone: 81 3 5285 1111. Fax: 81 3 5285 1161. E-mail: tesuzuki{at}nih.go.jp

{triangledown} Published ahead of print on 26 March 2008.

Journal of Virology, June 2008, p. 5715-5724, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02530-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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