SOCS1 and SOCS3 are targeted by hepatitis C virus core/gC1qR ligation to inhibit T-cell function.

T cells play an important role in the control of hepatitis C virus (HCV) infection. We have previously demonstrated that the HCV core inhibits T-cell responses through interaction with gC1qR. We show here that core proteins from chronic and resolved HCV patients differ in sequence, gC1qR-binding ability, and T-cell inhibition. Specifically, chronic core isolates bind to gC1qR more efficiently and inhibit T-cell proliferation as well as gamma interferon (IFN-) production more profoundly than resolved core isolates. This inhibition is mediated by the disruption of STAT phosphorylation through the induction of SOCS molecules. Silencing either SOCS1 or SOCS3 by small interfering RNA dramatically augments the production of IFN- in T cells, thereby abrogating the inhibitory effect of core. Additionally, the ability of core proteins from patients with chronic infections to induce SOCS proteins and suppress STAT activation greatly exceeds that of core proteins from patients with resolved infections. These results suggest that the HCV core/gC1qR-induced T-cell dys- function involves the induction of SOCS, a powerful inhibitor of cytokine signaling, which represents a novel mechanism by which a virus usurps the host machinery for persistence. Hepatitis C virus (HCV) is remarkable in evading host im- mune surveillance, resulting in persistent infections in the ma- jority of infected individuals that may progress to liver cirrhosis and hepatocellular carcinoma, thus becoming a leading cause of liver transplantation in the United States. Virus-mediated CD4 and CD8 T-cell dysfunction seems to play a pivotal role in the establishment of persistent HCV infection. In acute HCV infection, an early and sustained virus-specific T-cell response is critical for viral clearance (1, 20, 33). In contrast, chronic HCV patients display impaired virus-specific CD4 and CD8 T cells with lower proliferative and gamma inter- feron (IFN-)-producing capacities (13, 19, 35). This impaired T-cell function may contribute to increased susceptibility to secondary microbial pathogens, including viruses, bacteria, and parasites, during chronic HCV infection (4, 21). Despite ex- tensive investigations of HCV pathogenesis, it still remains unclear why some HCV patients exhibit effective T-cell re- sponses and clear the virus during acute infection, whereas others fail to do so and progress to chronic infection. HCV core, the first protein to be synthesized upon viral infec- tion, exhibits multiple functions, including the regulation of viral and cellular gene expression, induction of tumorigenesis, modulation of apoptosis, and suppression of host immunity (28). We have previously demonstrated that HCV core can inhibit T-cell proliferation through interaction with gC1qR on T lymphocytes (17, 36-38). This finding, in light of the obser- vation that free core particles circulate in the bloodstreams of HCV-infected patients (24, 25), is particularly noteworthy in HCV pathogenesis since the binding of C1q, the natural ligand