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Journal of Virology, November 2006, p. 11331-11342, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00104-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Diverse CD81 Proteins Support Hepatitis C Virus Infection{triangledown}

Mike Flint,1,{dagger}* Thomas von Hahn,1,{dagger} Jie Zhang,1 Michelle Farquhar,2 Christopher T. Jones,1 Peter Balfe,2 Charles M. Rice,1 and Jane A. McKeating2

Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, New York 10021,1 Division of Immunity and Infection, Institute of Biomedical Research, Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom2

Received 15 January 2006/ Accepted 9 August 2006

Hepatitis C virus (HCV) entry is dependent on CD81. To investigate whether the CD81 sequence is a determinant of HCV host range, we expressed a panel of diverse CD81 proteins and tested their ability to interact with HCV. CD81 large extracellular loop (LEL) sequences were expressed as recombinant proteins; the human and, to a low level, the African green monkey sequences bound soluble HCV E2 (sE2) and inhibited infection by retrovirus pseudotype particles bearing HCV glycoproteins (HCVpp). In contrast, mouse or rat CD81 proteins failed to bind sE2 or to inhibit HCVpp infection. However, CD81 proteins from all species, when expressed in HepG2 cells, conferred susceptibility to infection by HCVpp and cell culture-grown HCV to various levels, with the rat sequence being the least efficient. Recombinant human CD81 LEL inhibited HCVpp infectivity only if present during the virus-cell incubation, consistent with a role for CD81 after virus attachment. Amino acid changes that abrogate sE2 binding (I182F, N184Y, and F186S, alone or in combination) were introduced into human CD81. All three amino acid changes in human CD81 resulted in a molecule that still supported HCVpp infection, albeit with reduced efficiency. In summary, there is a remarkable plasticity in the range of CD81 sequences that can support HCV entry, suggesting that CD81 polymorphism may contribute to, but alone does not define, the HCV susceptibility of a species. In addition, the capacity to support viral entry is only partially reflected by assays measuring sE2 interaction with recombinant or full-length CD81 proteins.

* Corresponding author. Present address: Wyeth Research, 500 Arcola Road, S-1111, Collegeville, PA 19426. Phone: (484) 865-0356. Fax: (484) 865-9370. E-mail: flintm{at}wyeth.com.

{triangledown} Published ahead of print on 30 August 2006.

{dagger} These authors contributed equally to this paper.

Journal of Virology, November 2006, p. 11331-11342, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00104-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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