CD8+ T CELL REPROGRAMMING TO BOOST ANTIVIRAL POTENTIAL AGAINST CHRONIC INFECTION

PROJECT SUMMARY/ABSTRACT There is substantial evidence that stem-like CD8+ T cells have a central role in the natural control of chronic viral infection. For example, virus-specific CD8+ T cells from HIV-1 natural controllers have enhanced antiviral potential, related to the development of stemness properties, including high survival, polyfunctionality, and proliferative potential. Similar observations have been made for other chronic viral infections in humans, such as Hepatitis B virus (HBV). The development of stem-like memory CD8+ T cells thus appears crucial to achieving natural control of chronic viral infections. Considering the lack of cure for prevalent chronic viral infections such as HIV-1 and HBV, we propose that future therapies aiming at remission of these diseases require reprogramming CD8+ T cells to exhibit stemness properties, via cellular adoptive transfer or direct administration of immunomodulatory drugs. In previous studies, we optimized a system to reprogram HIV-specific CD8+ T cells from non-controller individuals to improve their functional qualities, using a GSK3 inhibitor. Given these findings, we hypothesize that HBV-specific CD8+ T cells from individuals with chronic infection will benefit from this reprogramming method and enhance their functional qualities. To further elucidate the effectiveness of such CD8+ T cell reprogramming to boost their antiviral functions in other chronic viral infections, here we aim to: i) Evaluate the impact of our established method of reprogramming on the antiviral potential of HBV- specific CD8+ T cells from individuals with chronic infection, in terms of cytokine production, proliferation, survival, and the response to immune checkpoint blockade; ii) To compare the functional profile of reprogrammed HBV-specific CD8+ T cells with cells derived from individuals who reached functional cure of HBV infection. The results of this proposal will help to better understand the therapeutic potential of CD8+ T cell reprogramming by targeting transcriptional and metabolic pathways, in the search for the remission of prevalent chronic viral infections.