Immune correlates of protection against hepacivirus persistence.

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Abstract Although direct acting antivirals can cure Hepatitis C virus (HCV) infection, a vaccine is necessary to stop new infections, and to prevent re-infections in the cured individuals. Studies in humans and chimpanzees suggest that both T cells and neutralizing antibodies (nAb) can play an important role in the clearance of HCV infection. However, further progress on HCV vaccine development has been stymied by a lack of animal models. Notably, the nature, breadth, and relative contribution of humoral and cellular immunity in determining the outcomes of HCV infection remain poorly understood. We recently showed that a rat hepacivirus (HCV-like virus), RHV, shares the hallmarks of HCV infection and immunity. A majority of fully-immunocompetent rats develop lifelong viral persistence, and thus rats are appropriate models for “proof-of-concept” vaccination studies to prevent HCV- like viral persistence, the desired goal of HCV vaccines. We further validated this model by determining that like reported from HCV studies in chimpanzees, rats vaccinated using an Adenovirus expressing RHV non-structural (NS) proteins develop partial protection against persistence of a homologous RHV strain (Nature communications, PMC6405742). Interestingly, we observed that the vaccinated rats that cleared a homologous virus developed more efficient and broader immunity for homologous and heterologous viruses, and T cell escape variants. These results suggest that the short- term viral infection either enhances T cell immunity or generates nAbs, or both, to confer effective immunity against heterologous viruses. Most importantly, these results are promising for defining the nature of immunity that confers effective protection against persistent infection of genetically diverse viruses, like HCV variants. The overall goal of this project is to define the immune correlates of protection against hepacivirus persistence. Specific aim-1 is to define the T cell correlates of protection against hepacivirus persistence. Our hypothesis is that the nature and breadth of virus-specific T cells determines the fate of hepacivirus infections. Specific aim-2 is to study the role of envelope proteins (E1/E2) induced immunity and importance of nAbs in virus clearance. Our hypothesis is that a vaccination approach using a combination of NS and E1E2 vaccines will increase the immunity against viral persistence. Specific Aim- 3 is to define the breadth of vaccine induced immunity, and to identify the viral determinants of vaccine failure. Our hypothesis is that vaccination can prevent persistence of genetically diverse viruses that share only a few T cell epitopes. The proposed dissection of vaccine and short-term viral infection conferred immunity is necessary to understand the relative contributions of T and B cells in hepacivirus clearance, and this knowledge can help in conceptualizing an effective vaccination strategy for HCV. Finally, the proposed characterization of T and B cell immunity in this unique model of life-long persistent RNA virus infection will pave the way for testing of newer vaccination approaches (like RNA vaccines) to prevent chronic virus infection.