Characterizing intact proviral HIV-1 reservoir size and determinants of reservoir dynamics in African populations

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Project Summary Antiretroviral treatment is unable to clear HIV-1 infection because a highly stable latent viral reservoir persists in the host. Key areas of interest with respect to HIV-1 eradication strategies include latent reservoir establishment, size and make-up. A considerable amount is now known about these key areas in subtype B-infected American men, yet there remains limited knowledge in the most affected population, subtype C-infected South African women, or in African populations in general. Population differences may exist with respect to reservoir characteristics, and eradication strategies would need to take such differences into account. Characterization of the HIV-1 reservoir in the African context therefore represents a much needed area of attention. This project proposes to firstly address the need for implementation of a high-throughput, accurate reservoir sizing method in South Africa through optimization of the newly developed intact proviral DNA assay (IPDA) for subtype C HIV-1. This method will be applied to more than 200 women from KwaZulu Natal. Reservoir size in these women will be compared to that of individuals from Ugandan and American cohorts using the same assay to evaulate reservoir differences across populations. This project will also investigate a role for the viral factors Nef and the long terminal repeat, which are drivers of immune evasion and gene transcription respectively, in reservoir size and make-up in a subset of these women. Finally, we will explore the contribution of viral variants from the blood and cervix to the long-lived reservoir in these women using Bayesian evolutionary analyses. We hypothesize that Nef-mediated MHC-I downregulation and LTR activity have independent effects on reservoir size and distribution, and these effects differ according to infecting subtype and study population. This project will allow for comparison of reservoir size across populations using a standardized assay and will evaluate determinants of size and kinetics of establishment.