Grant: Project Grant

Hepatitis C virus (HCV) infection is still a public health priority as many who are infected remain undiagnosed and continue to infect others leading to increase infection rates in association with the opioid epidemic. Direct acting antivirals offer complete cure in >95% of infected individuals but do not prevent reinfection. Hence, there is an urgent need for vaccines that can protect against this virus. Unfortunately, despite our knowledge about the immune response against HCV, we still do not have an effective vaccine. Results from the only vaccine candidate that made it into a large scale (Phase 2) clinical trial did not show any protection in people who use drugs who are at high-risk of HCV infection. This means that we have to understand better the immune factors that protect against HCV and how we can manipulate them to enhance protective immunity. This project will build on our recent results where we examined early changes in the gene profile of virus-specific immune cells in individuals who went on to either resolve their HCV infection or became chronic. This analysis provided us with three potential molecules/cells that were increased in resolvers as compared to chronics and that maybe key to determining the outcome of HCV infection. These are: an immune mediator of inflammation (cytokine) known as IL-32 and, two immune cell populations known as Mucosal-associated invariant T (MAIT) and cytotoxic CD4 T cells. In this proposal we will examine the activation of these three different paths independently as well as relative to each other to understand how they collaborate together to generate an effective immune response against HCV. We will use chemical compounds or other biologicals to boost the function of these pathways in immune cells from individuals who are unable to clear the virus. Such strategies can be combined with different future vaccine candidates to enhance their immunogenicity and protective capacity.