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Journal of Virology, December 2007, p. 13783-13793, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01091-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Human Apolipoprotein E Is Required for Infectivity and Production of Hepatitis C Virus in Cell Culture{triangledown}

Kyung-Soo Chang,{dagger} Jieyun Jiang,{dagger} Zhaohui Cai,{dagger} and Guangxiang Luo*

Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, Kentucky 40536

Received 21 May 2007/ Accepted 21 September 2007

Recent advances in reverse genetics of hepatitis C virus (HCV) made it possible to determine the properties and biochemical compositions of HCV virions. Sedimentation analysis and characterization of HCV RNA-containing particles produced in the cultured cells revealed that HCV virions cover a large range of heterogeneous densities in sucrose gradient. The fractions of low densities are infectious, while the higher-density fractions containing the majority of HCV virion RNA are not. HCV core protein and apolipoprotein B and apolipoprotein E (apoE) were detected in the infectious HCV virions. The level of apoE correlates very well with HCV infectivity. Both apoE- and HCV E2-specific monoclonal antibodies precipitated HCV, demonstrating that HCV virions contain apoE and E2 proteins. apoE-specific monoclonal antibodies efficiently neutralized HCV infectivity in a dose-dependent manner, resulting in a reduction of infectious HCV by nearly 4 orders of magnitude. The knockdown of apoE expression by specific small interfering RNAs (siRNAs) remarkably reduced the levels of intracellular as well as secreted HCV virions. The apoE siRNA suppressed HCV production by more than 100-fold at 50 nM. These findings demonstrate that apoE is required for HCV virion infectivity and production, suggesting that HCV virions are assembled as apoE-enriched lipoprotein particles. Our findings also identified apoE as a novel target for discovery and development of antiviral drugs and monoclonal antibodies to suppress HCV virion formation and infection.

* Corresponding author. Mailing address: Departments of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536. Phone: (859) 257-5577. Fax: (859) 257-8994. E-mail: gluo0{at}uky.edu

{triangledown} Published ahead of print on 3 October 2007.

{dagger} These authors contributed equally to this work.

Journal of Virology, December 2007, p. 13783-13793, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01091-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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