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Work package 6

Modulators of adaptive immune response in HCV infection

Hepatitis C virus (HCV), a single stranded positive RNA virus of the Flaviviridae family, chronically infects 3% of the world’s population and often results in cirrhosis or liver cancer (Ghany et al., Hepatology, 2011). The mechanism by which HCV causes chronic infection in the majority of infected persons remains unclear. It is likely that HCV activates different mechanisms to evade host defenses, although most literature has focused on the role of interference with the endogenous IFN system, suppressions of host-immune responses by HCV proteins through interference with T-cell function, and HCV-quasispecies variability (Farci et al., Science, 2000; Foy et al., Science, 2003; Rehermann, J Clin Invest, 2009; Tang et al., Clin Sci, 2009). Clinically-oriented studies confirmed an important role of cytokines and chemokines in the response to antiviral/immunomodulatory treatment, as recently shown by our group (Kurelac et al., J Interferon Cytokine Res, 2012).

Given the critical role of DCs in priming T cell responses, DC in vitro models and DCs from chronically infected patients have been extensively studied, with the idea that HCV-mediated inhibition of antigen-presenting functions could result in inefficient antiviral T-cell responses (Bain et al., Gastroenterology, 2001; Dolganiuc et al., J Immunol, 2003; Accapezzato et al., Eur J Immunol, 2004). Conflicting evidence resulted from these studies; nevertheless, the ones that revealed a general subversion of both T-cells and DCs functions faced a problem that chronically infected individuals are not globally immunodeficient and have a relatively high level of endogenous IFNs. The overall goal is to identify and characterise molecules involved in the regulation of immune responses and development of the tolerance. Study subjects will be patients with chronic hepatitis C infection. Altogether, this study will describe the role of selected biological response modifiers (e.g. IL-23, IDO1) in the pathogenesis of HCV, response to antiviral/immunomodulatory treatment of chronic hepatitis C. This will lead us to identification of proteins that can easily be measured in the patients’ serum, therefore linking the basic and clinical sciences.

(Photo: Hepatitis C virus purified from cell culture, Center for the Study of Hepatitis C, The Rockefeller University.)