ObjectiveHepatitis A virus (HAV) infections are considered not to trigger an innate immune responsein vivo, in contrast to hepatitis C virus (HCV). This lack of immune induction has been imputed to strong immune counteraction by HAV proteases 3CD and 3ABC. We aimed at elucidating the mechanisms of innate immune induction and counteraction by HAV and HCVin vivoandin vitro.DesignuPA-SCID mice with humanized liver were infected with HAV and HCV. Hepatic cell culture models were used to assess HAV and HCV sensing by TLR3 and RIG-I/MDA5, respectively. Cleavage of the adaptor proteins TRIF and MAVS was analyzed by transient and stable expression of HAV and HCV proteases and virus infection.ResultsWe detected similar levels of Interferon stimulated genes (ISGs) induction in hepatocytes of HAV and HCV infected human liver chimeric mice. In cell culture, HAV induced ISGs exclusively upon sensing by MDA5 and dependent on LGP2. TRIF and MAVS were only partially cleaved by HAV 3ABC and 3CD, not sufficiently to abrogate signalling. In contrast, HCV NS3-4A efficiently degraded MAVS, as previously reported, whereas TRIF was not cleaved.ConclusionsHAV induces an innate immune response in hepatocytes via MDA5/LGP2, with limited control of both pathways by proteolytic cleavage. HCV activates TLR3 and lacks TRIF cleavage, suggesting that this pathway mainly contributes to HCV induced antiviral response in hepatocytes. Our results shed new light on induction and counteraction of innate immunity by HAV and HCV and their potential contribution to clearance and persistence.SIGNIFICANCE OF THIS STUDYWhat is already known on this topic?—Despite sharing biological and molecular similarities, HAV infections are always cleared while HCV infections persist in most cases.—In infected chimpanzees HAV does not trigger a strong innate immune response, as opposed to HCV. This has been imputed to the action of HAV proteases abrogating the signalling pathways.—Physiologicalin vitroandin vivomodels, based on human hepatocytes, to assess HAV and HCV mechanisms of induction and interference of innate immunity are still missing.What this study adds—HAV induces an innate immune responsein vitroandin vivo, in systems with intact signalling pathways and devoid of adaptive immunity.—HAV 3ABC and 3CD proteases do not abolish the host innate immune response.—HCV NS3-4A protease disrupts the RLRs pathways, but cannot cleave TRIF and has no impact on TLR3 response.How this study might affect research, practice or policy—This study offers a comprehensive, side-by-side investigation on HAV and HCV infections in physiological models which recapitulate a cytokine response in the human liver, and allows a precise assessment of the viral interference related to the function of the respective signalling pathways.—Our results elucidate mechanisms, so far controversial or poorly investigated, thus contributing to our understanding of HAV clearance and HCV persistence.

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