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Journal of Virology, July 2005, p. 8079-8089, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8079-8089.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus E2-CD81 Interaction Induces Hypermutation of the Immunoglobulin Gene in B Cells{dagger}

Keigo Machida,1 Kevin T.-H. Cheng,1 Nicole Pavio,1 Vicky M.-H. Sung,1 and Michael M. C. Lai1,2*

Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Ave., Los Angeles, California 90033,1 Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan2

Received 26 November 2004/ Accepted 7 March 2005

Hepatitis C virus (HCV) is one of the leading causes of chronic liver diseases and B-lymphocyte proliferative disorders, including mixed cryoglobulinemia and B-cell lymphoma. It has been suggested that HCV infects human cells through the interaction of its envelope glycoprotein E2 with a tetraspanin molecule CD81, the putative viral receptor. Here, we show that the engagement of B cells by purified E2 induced double-strand DNA breaks specifically in the variable region of immunoglobulin (VH) gene locus, leading to hypermutation in the VH genes of B cells. Other gene loci were not affected. Preincubation with the anti-CD81 monoclonal antibody blocked this effect. E2-CD81 interaction on B cells triggered the enhanced expression of activation-induced cytidine deaminase (AID) and also stimulated the production of tumor necrosis factor alpha. Knockdown of AID by the specific small interfering RNA blocked the E2-induced double-strand DNA breaks and hypermutation of the VH gene. These findings suggest that HCV infection, through E2-CD81 interaction, may modulate host's innate or adaptive immune response by activation of AID and hypermutation of immunoglobulin gene in B cells, leading to HCV-associated B-cell lymphoproliferative diseases.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Ave., Los Angeles, CA 90033. Phone: (323) 442-1748. Fax: (323) 442-1721. E-mail: michlai{at}usc.edu.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, July 2005, p. 8079-8089, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8079-8089.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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