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Journal of Virology, August 2004, p. 8496-8505, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8496-8505.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Diverse Hepatitis C Virus Glycoproteins Mediate Viral Infection in a CD81-Dependent Manner

J. A. McKeating,1* L. Q. Zhang,2,3 C. Logvinoff,1 M. Flint,1 J. Zhang,1 J. Yu,2 D. Butera,1 D. D. Ho,2 L. B. Dustin,1 C. M. Rice,1 and P. Balfe4

Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10021,1 Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016,2 AIDS Research Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China 100730,3 Division of Infectious Diseases, Columbia University, New York, New York 100324

Received 12 February 2004/ Accepted 8 April 2004

We recently reported that retroviral pseudotypes bearing the hepatitis C virus (HCV) strain H and Con1 glycoproteins, genotype 1a and 1b, respectively, require CD81 as a coreceptor for virus-cell entry and infection. Soluble truncated E2 cloned from a number of diverse HCV genotypes fail to interact with CD81, suggesting that viruses of diverse origin may utilize different receptors and display altered cell tropism. We have used the pseudotyping system to study the tropism of viruses bearing diverse HCV glycoproteins. Viruses bearing these glycoproteins showed a 150-fold range in infectivity for hepatoma cells and failed to infect lymphoid cells. The level of glycoprotein incorporation into particles varied considerably between strains, generally reflecting the E2 expression level within transfected cells. However, differences in glycoprotein incorporation were not associated with virus infectivity, suggesting that infectivity is not limited by the absolute level of glycoprotein. All HCV pseudotypes failed to infect HepG2 cells and yet infected the same cells after transduction to express human CD81, confirming the critical role of CD81 in HCV infection. Interestingly, these HCV pseudotypes differed in their ability to infect HepG2 cells expressing a panel of CD81 variants, suggesting subtle differences in the interaction of CD81 residues with diverse viral glycoproteins. Our current model of HCV infection suggests that CD81, together with additional unknown liver specific receptor(s), mediate the virus-cell entry process.

* Corresponding author. Mailing address: Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: (212) 327-7066. Fax: (212) 327-7048. E-mail: mckeatj{at}rockefeller.edu.

Journal of Virology, August 2004, p. 8496-8505, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8496-8505.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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