Control of Long-lived HIV Cellular Reservoirs in memory CD4+ T cells by Bach2

Despite effective antiretroviral therapy (ART), HIV-1 mainly persists in a small pool of latently infected, resting memory CD4+ T cells in people living with HIV-1 (PLWH). Virus eradication with ART alone will not be possible. The stability of the viral reservoir is a consequence of infection of cells that either have expanded or are destined to expand in response to cognate antigens or cytokines. CCR5 and CXCR4 are two co-receptors for HIV-1 entry. CCR5-tropic virus is critical for the establishment of infection and dominates the pool of viruses in blood and tissues early after infection. In PLWH, latent HIV-1 is predominantly CCR5-tropic, which is a reflection of selective transmission and dominant replication of CCR5-tropic virus before ART initiation. CCR5 is expressed predominantly by terminally differentiated CD4+ T cells which lose proliferation capacity and are prone to cell death. To seed the latent reservoir, CCR5-expressing CD4+ T cells are infected, carry integrated and transcriptionally silent HIV-1 provirus, and differentiate into long- lived memory cells. To maintain the latent reservoir, cells carry integrated HIV-1 proviruses proliferate despite potential viral cytopathic effects or immune clearance. Therefore, studies on the mechanisms suppressing terminal differentiation of CCR5+CD4+ T cells are significant. In this study, we plan to address the following three questions. 1) How does Bach2 inhibit terminal differentiation of CCR5+CD4+ T cells and how does it impact viral reservoir seeding in humanized mice? 2) Can Bach2-mediated differentiation of CCR5+CD4+ T cells results in long-lived memory cells with proliferation capacity? 3) Can we target Bach2 or its downstream molecules to prevent HIV reservoir seeding? Understanding this process can help us develop strategies to block seeding or expansion of the stable viral latent reservoirs in vivo. Project Number: 1R56AI186666-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Priya Pal | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $499,550 | Activity Code: R56 | Study Section: HIV Molecular Virology, Cell Biology, and Drug Development Study Section[HVCD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R56AI18666601A1