HEPATG · AUTOPHAGY AND VIRULENCE OF HEPATITIS C VIRUS

Autophagy is a major intracellular pathway for cellular homeostasis. It also plays an essential role in antiviral response against diverse pathogens. Indeed, in addition to the removal of viral protein aggregates from the cells, autophagy is emerging as a key regulator of viral propagation by regulating positively or negatively the secretion of interferon α/β (IFNα/β) and inflammatory molecules, known to be essential to initiate antiviral responses. However, certain pathogens such as, for example, the hepatitis C virus (HCV), which chronically infects over 130 million peoples in the word and thus has a substantial impact on public health, have developed mechanisms to inhibit the completion of autophagy. Moreover, we demonstrated that HCV even uses autophagy proteins for the translation of incoming viral genomes in newly infected cells (Dreux et al., PNAS 2009). Thus, this CIG proposal is based on our princeps data and aims at determining the functional relationships between autophagy and HCV. Therefore, we will define the molecular mechanism whereby HCV co-opt the autophagy regulators to initiate the translation of its genome. In addition, we will decipher the mechanism of inhibition of autophagy completion by this virus and its impact on viral replication. Furthermore, we will analyze the regulation by autophagy proteins of antiviral molecules production during HCV infection. Finally, this project will entail at determining the role of autophagy-virus interplay during in vivo infection using mice reconstituted with a human liver that we recently established in the lab and that are robustly susceptible to HCV infection. Those complementary analyses will permit to further understand the regulation of viral infection by autophagy and will contribute to the design of better therapeutic strategies against HCV.