Characterizing HIV reservoir in HIV-2, and HIV-1 and HIV-2 dual infections

About This Grant

PROJECT SUMMARY The persistence of latent viral reservoirs is a major obstacle to curing HIV, as it causes viral rebound when antiretroviral therapy (ART) is interrupted. Current strategies for an HIV cure, such as "shock and kill," "block and lock," broadly neutralizing antibodies, chimeric antigen receptors, and therapeutic vaccines, focus largely on subtype B and overlook Africa, which bears the highest burden of HIV. Africa, home to two-thirds of global HIV cases, has significant genetic diversity in HIV subtypes, including HIV-1, recombinant forms, and HIV-2. HIV-2, found mainly in West Africa, constitutes 10–20% of regional HIV cases, yet little is known about its latent reservoirs, particularly in dual HIV-1/2 infections. This study aims to address this gap by investigating HIV-2 latent reservoirs and their interactions with HIV-1 in dual infections, focusing on a cohort in Ghana. A cohort of 74 virologically suppressed individuals with dual infections will be used. The team’s expertise includes developing assays to quantify viral DNA and RNA specific to HIV-2. Aim 1 focuses on quantifying reservoir sizes in CD4+ T-cell subsets (central, transitional, and effector memory) and monocytes across HIV-1, HIV-2, and dual infections. Previous studies have explored reservoirs in ART-naïve people living with HIV-2 but not in virologically suppressed or dual-infected individuals. Methods include cell-associated DNA PCR, RNA analysis, quantitative viral outgrowth assays (QVOA) and intact proviral DNA assay (IPDA). Aim 2 will create an HIV-2 latency model using cell lines like Jurkat and THP-1 and test latency-reversing agents (LRAs) on ex-vivo samples from virologically suppressed people. The team will adapt existing fluorescence-based tools for HIV-2 and measure viral reactivation using gag mRNA quantification. The outcomes will provide critical insights into the HIV-2 reservoir and its impact on HIV-1 in dual infections, laying the groundwork for cure strategies that extend to the USA and globally, as HIV-2 has been identified in other regions, including the USA, due to migration. Understanding HIV-2 reservoir dynamics and latency reactivation will inform the development of new ways to tackle HIV-1 which will benefit PWH in the USA as well. Findings from the study could advance global HIV cure research on reservoir characteristics, measurement tools, and therapeutic approaches that address different viral subtypes and dual infections. The proposal aligns with exploratory R21 mechanisms and has the potential to significantly advance HIV cure research in the USA and globally.