Defining the biological relevance of HIV specific HLA-E restricted CD8 T cell responses

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PROJECT SUMMARY HLA-E restricted CD8 T cells specific to a diverse repertoire of viral and bacterial peptides have been reported indicating their role in adaptive immunity. Due to their limited polymorphism, peptide presentation through HLA- E can be considered advantageous for vaccine design. In SIV/macaque studies, protection from pathogenic SIV challenge was observed in 50% rhesus macaques vaccinated with an RhCMV based vector. This unprecedented protection was independent of antibodies and attributed in part to an induction of MHC-E restricted CD8 T cells. Despite promising findings from several viral infections, role of HLA-E specific CD8 T cells in HIV has been grossly understudied. In fact, no study to date has examined the role of HLA-E restricted CD8 T cells (E-CD8s) in HIV infection and vaccination. The only published data to suggest the presence of HLA-E restricted HIV- specific CD8 T cells are experiments demonstrating that HIV peptides can bind to HLA-E. Since HLA-Ia and E are ubiquitously co-expressed, a significant gap in our knowledge has largely been due to absence of biological reagents to delineate the contribution of HLA-Ia vs. HLA-E alleles in HIV. Our group has generated HLA-E specific reagents to address the missing gaps in information on the relevance of HLA-E restricted CD8 T cells targeting HIV. Our preliminary data shows that HLA-E restricted CD8 T cell responses specific for 2 epitopes in Gag can be detected in chronic HIV infection. In many cases, these responses were not only restricted by E allele but also by classical HLA-Ia alleles. Furthermore, in small subset of HIV infected individuals, we observed that in individuals who control virus, without any ART i.e. controllers mounted HLA-E restricted CD8 T cell responses that were polyfunctional and higher in magnitude. In comparison, viremic individuals on ART mounted lower magnitude of HLA-E restricted CD8 T cell responses that mainly induced IFN-γ and CD107 expression. We also show that Gag epitopes are presented by HLA-E in an HIV infected cell. Finally, our pilot data shows priming of HLA-E restricted CD8 T cell responses in HIV seronegative donors. The latter underscores the need to see if these responses are induced by preventative vaccines and if not how can these be optimized and harnessed for effective HIV vaccines. Our strong preliminary findings are foundational for the work proposed in the current grant. Our overarching goal is to address the central question of whether HIV is impacted by the frequency, breadth, and functionality of HLA-E restricted CD8 T cells. Based on our data, we hypothesize that dually restricted CD8 T cells will be associated with a broader response which would be useful for a preventative vaccine and make HIV escape more difficult. Aim 1, determines the relevance of HLA-E restricted CD8 T cells in HIV infection and vaccination. We will use samples from acute/chronic infection and 2 prior CTL based HIV vaccines. Aim 2 uses single cell based analyses to determine αβTCR repertoire and gene expression patterns of HIV specific CD8 T cells restricted by HLA-E and how these molecular signatures relate to viral control.