Tu177 - The NLRC5/HLA-I Axis : A New Target to Elicit a Potent CD8+ T Cell Response Towards Early HIV-infected Cells?

Abstract Text: The absence of a cure or vaccine for HIV highlights the important need for innovative therapeutic strategies. Interestingly, rare patients called HIV controllers limit the viral replication with an effective immune response, including a CD8+ T cell response targeting early infected CD4+ T cells. This response is mediated by the recognition of viral antigens from incoming particles through HLA-I pathway.

We hypothesize that enhancing the amount of presented viral antigens from incoming particles on infected CD4+ T cells via upregulation of the HLA-I pathway could enhance the CD8+ T cell response, thereby improving viral control. NLRC5, a key transactivator of the HLA-I pathway, is a promising candidate for this purpose. Notably, HIV proteins have been shown to downregulate NLRC5 expression in microglia, while epigenetic modifications of the NLRC5 gene have been observed in people living with HIV, potentially suggesting a viral immune evasion mechanism similar to that of SARS-CoV-2.

Our preliminary data reveal that HIV infection induces epigenetic modifications of the NLRC5 gene in people living with HIV as well as transcriptomic and protein expression changes in CD4+ T cells in vitro. We also developed tools to modulate NLRC5 expression in CD4+ T cells and we are investigating its impact on CD8+ T cell responses. These findings will then be confirmed ex vivo using cells from people living with HIV.

By elucidating the role of NLRC5 in viral antigen presentation and CD8+ T cell response, our study aims to advance novel strategies for enhancing immune control in HIV infection.