BACH2 promotes seeding and establishment of long-lived HIV-1 reservoir in memory CD4⁺ T cells

Despite antiretroviral therapy, HIV-1 mainly persists in memory CD4⁺ T cells in people living with HIV-1. Most long-lived viral reservoir cells are infected by the virus near the time of therapy initiation. A better understanding of the early events in viral reservoir seeding presents opportunities for preventing latent reservoir formation. Here, we demonstrate that CD4⁺ T cells expressing CCR5, permissive to HIV-1 infection, are effector or terminally differentiated cells. BTB domain and CNC homolog 2 (BACH2) is expressed by a small subset of CCR5⁺ cells and reverses their terminal differentiation. BACH2-mediated memory differentiation is impeded due to heightened inflammation before treatment initiation. Mice with a BACH2-knockout human immune system have a reduced frequency of HIV-1 reservoir cells and do not experience virus rebound after treatment discontinuation. Our study reveals that BACH2 is essential to the seeding and establishment of long-lived HIV-1 reservoir in memory CD4⁺ T cells.