title: Hepatitis C virus E2-CD81 interaction induces hypermutation of the immunoglobulin gene in B cells.
abstract: 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 (V(H)) gene locus, leading to hypermutation in the V(H) 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 V(H) 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.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, 2011 Zonal Ave., Los Angeles, California 90033, USA.
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
authors.forename: Kevin T-H
authors.initials: KT
authors.lastname: Cheng
authors.forename: Nicole
authors.initials: N
authors.lastname: Pavio
authors.forename: Vicky M-H
authors.initials: VM
authors.lastname: Sung
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Lai
mesh_terms: D015703:Antigens, CD / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D005803:Genes, Immunoglobulin; D016174:Hepacivirus; D006801:Humans; D008113:Liver Neoplasms; D020133:Reverse Transcriptase Polymerase Chain Reaction; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins