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Journal of Virology, October 2004, p. 11393-11400, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.11393-11400.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

An N-Terminal Amphipathic Helix in Hepatitis C Virus (HCV) NS4B Mediates Membrane Association, Correct Localization of Replication Complex Proteins, and HCV RNA Replication

Menashe Elazar,1 Ping Liu,1,2 Charles M. Rice,3 and Jeffrey S. Glenn1,2*

Division of Gastroenterology and Hepatology, Stanford University School of Medicine,1 Veterans Administration Medical Center, Palo Alto, California,2 Center for the Study of Hepatitis C, Rockefeller University, New York, New York3

Received 13 February 2004/ Accepted 25 May 2004

Like other positive-strand RNA viruses, hepatitis C virus (HCV) is believed to replicate its RNA in association with host cell cytoplasmic membranes. Because of its association with such membranes, NS4B, one of the virus's nonstructural proteins, may play an important role in this process, although the mechanistic details are not well understood. We identified a putative N-terminal amphipathic helix (AH) in NS4B that mediates membrane association. Introduction of site-directed mutations designed to disrupt the hydrophobic face of the AH abolishes the AH's ability to mediate membrane association. An AH in NS4B is conserved across HCV isolates. Completely disrupting the amphipathic nature of NS4B's N-terminal helix abolished HCV RNA replication, whereas partial disruption resulted in an intermediate level of replication. Finally, immunofluorescence studies revealed that HCV replication complex components were mislocalized in the AH-disrupted mutant. These results identify a key membrane-targeting domain which can form the basis for developing novel antiviral strategies.

* Corresponding author. Mailing address: Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CCSR Building, Room 3115, 269 Campus Dr., Palo Alto, CA 94305-5187. Phone: (650) 725-3373. Fax: (650) 723-3032. E-mail: jeffrey.glenn{at}stanford.edu.

Journal of Virology, October 2004, p. 11393-11400, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.11393-11400.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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