Grant: Catalyst Grant: Innovation in HIV Vaccine and HIV Cure Research

Persistence of latent HIV-1 reservoirs in rare subsets of long lived memory CD4+ T-cells represents one major barrier to eradication in the era of viral suppressive antiretroviral therapy. Different approaches are now under investigation to reactivate HIV from latent reservoirs so that these cells can be subsequently eliminated by immunological mechanisms. However, major limits of these approaches include lack of specificity and relatively high toxicity. In this context, the phenotypic identification of HIV cellular reservoirs is a major research priority for the design of targeted approaches toward eradication. Th17 cells represent a newly discovered lineage of memory CD4+ T-cell highly permissive to HIV infection. Depletion of Th17 cells is associated with deficient mucosal immunity against pathogens, microbial translocation, chronic immune activation and disease progression. Th17 cells are preserved in the gut-associated lymphoid tissues of HIV-infected slow progressors, thus emphasizing the critical role played by these cells in controlling disease progression. The recent phenotypic identification of naive Th17 precursors (CD25+CD127-FoxP3+) raised the possibility that Th17 deficiency may be caused by defects in naive Th17 precursors. In this proposal we will investigate the contribution of naive Th17 precursors to HIV pathogenesis in cohorts of individuals with rapid and slow disease progression. We will use state-of-the-art techniques in polychromatic flow cytometry to sort rare subsets of naïve Th17 precursors and real-time PCR to detect different forms of early reverse transcripts and integrated HIV-DNA. We will use Fluorescence in situ hybridization for visual analysis of viral genomic RNA in combination with different cellular markers. The identification of naive Th17 precursors as major contributors to HIV reservoir establishment/persistence will permit the design of new targeted therapies toward HIV eradication.