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Journal of Virology, June 2004, p. 6409-6419, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6409-6419.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Direct Binding of Hepatitis C Virus Core to gC1qR on CD4+ and CD8+ T Cells Leads to Impaired Activation of Lck and Akt

Zhi Qiang Yao,1,2 Audrey Eisen-Vandervelde,1,3 Stephen N. Waggoner,1,3 Evan M. Cale,1 and Young S. Hahn1,2,3*

Beirne Carter Center for Immunology Research,1 Department of Microbiology,3 Department of Pathology, University of Virginia, Charlottesville, Virginia 229082

Received 26 November 2003/ Accepted 12 February 2004

Complement plays a pivotal role in the regulation of innate and adaptive immunity. It has been shown that the binding of C1q, a natural ligand of gC1qR, on T cells inhibits their proliferation. Here, we demonstrate that direct binding of the hepatitis C virus (HCV) core to gC1qR on T cells leads to impaired Lck/Akt activation and T-cell function. The HCV core associates with the surface of T cells specifically via gC1qR, as this binding is inhibited by the addition of either anti-gC1qR antibody or soluble gC1qR. The binding affinity constant of core protein for gC1qR, as determined by BIAcore analysis, is 3.8 x 10–7 M. The specificity of the HCV core-gC1qR interaction is confirmed by reduced core binding on Molt-4 T cells treated with gC1qR-silencing small interfering RNA and enhanced core binding on GPC-16 guinea pig cells transfected with human gC1qR. Interestingly, gC1qR is expressed at higher levels on CD8+ than on CD4+ T cells, resulting in more severe core-induced suppression of the CD8+-T-cell population. Importantly, T-cell receptor-mediated activation of the Src kinases Lck and ZAP-70 but not Fyn and the phosphorylation of Akt are impaired by the HCV core, suggesting that it inhibits the very early events of T-cell activation.

* Corresponding author. Mailing address: Department of Microbiology and Beirne Carter Center, University of Virginia, HSC Box 801386, Charlottesville, VA 22908. Phone: (434) 924-1155. Fax: (434) 924-1221. E-mail: ysh5e{at}virginia.edu.

Journal of Virology, June 2004, p. 6409-6419, Vol. 78, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.12.6409-6419.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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