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J. Biol. Chem., Vol. 279, Issue 42, 43479-43486, October 15, 2004

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Hepatitis C Virus Core Selectively Suppresses Interleukin-12 Synthesis in Human Macrophages by Interfering with AP-1 Activation^*

Audrey L. Eisen-Vandervelde, Stephen N. Waggoner, Zhi Qiang Yao¶, Evan M. Cale, Chang S. Hahn||, and Young S. Hahn¶**

From the Beirne Carter Center for Immunology Research and the Departments of Microbiology and ^¶Pathology, University of Virginia, Charlottesville, Virginia 22908 and ^||Immunology Platform, Aventis Pharmaceuticals, Bridgewater, NJ 08807

Hepatitis C virus (HCV) is remarkably efficient at establishing persistent infection, suggesting that it has evolved one or more strategies aimed at evading the host immune response. T cell responses, including interferon- production, are severely suppressed in chronic HCV patients. The HCV core protein has been previously shown to circulate in the bloodstream of HCV-infected patients and inhibit host immunity through an interaction with gC1qR. To determine the role of the HCV core-gC1qR interaction in modulation of inflammatory cytokine production, we examined interleukin (IL)-12 production, which is critical for the induction of interferon- synthesis, in lipopolysaccharide-stimulated human monocyte/macrophages. We found that core protein binds the gC1qR displayed on the cell surface of monocyte/macrophages and inhibits the production of IL-12p70 upon lipopolysaccharide stimulation. This inhibition was found to be selective in that HCV core failed to affect the production of IL-6, IL-8, IL-1, and tumor necrosis factor . In addition, suppression of IL-12 production by core protein occurred at the transcriptional level by inhibition of IL-12p40 mRNA synthesis. Importantly, core-induced inhibition of IL-12p40 mRNA synthesis resulted from impaired activation of AP-1 rather than enhanced IL-10 production. These results suggest that the HCV core-gC1qR interaction may play a pivotal role in establishing persistent infection by dampening T_H1 responses.

Received for publication, July 7, 2004 , and in revised form, July 29, 2004.

^* This work was supported by National Institutes of Health Grant DK66754. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Microbiology, Pathology, and Beirne Carter Center, University of Virginia HSC, Box 801386, Charlottesville, VA 22903. Tel.: 434-924-1155; Fax: 434-924-1221; E-mail: ysh5e{at}virginia.edu.

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