Abstract
HIV persists in infected individuals despite effective antiretroviral therapy due to the rapid establishment of a latent HIV reservoir, mainly composed of quiescent memory CD4+ T cells1–3. The mechanisms governing the formation of the latent reservoir remain poorly understood. It is commonly assumed that entry of HIV into latency is a rare and random event associated with sporadic infection of effector T-cells transitioning to a memory phenotype4–8. Using human primary CD4+ T cell models, we show instead, that HIV infection itself triggers a strong transcriptomic remodeling that results in activation of a quiescence program, including downregulation of cellular proliferation and metabolic pathways. This transcriptional program is initiated by KLF2, a key regulator of quiescence, along with activation of the p53 pathway and downregulation of MYC. Loss and gain of function studies confirmed that KLF2 and p53 signaling are responsible for the downregulation of MYC and proliferation pathways, and consequently, proviral transcriptional silencing. Thus, HIV infection per se, enhances the formation of the latent reservoir in T-cells, ensuring viral persistence in infected individuals. These findings identify a new and unexpected mechanism for the formation of the latent HIV reservoir, and broaden the repertoire of strategies through which viruses can control the host cell to their advantage.
Small Molecules and Big Killers: The Challenge of Eliminating the Latent HIV Reservoir