Papers in the Biological Sciences
Date of this Version
Li et al., iScience 26, 105743 January 20, 2023 © 2022 The Author(s). https://doi.org/10.1016/ j.isci.2022.105743
HIV reservoirs are extremely stable and pose a tremendous challenge to clear HIV infection. Here, we demonstrate that activation of ISR/ATF4 signaling reverses HIV latency, which also selectively eliminates HIV+ cells in primary CD4+T cell model of latency without effect on HIV-negative CD4+T cells. The reduction of HIV+ cells is associated with apoptosis enhancement, but surprisingly is largely seen in HIV-infected cells in which gag-pol RNA transcripts are detected in HIV RNA-induced ATF4/IFIT signaling. In resting CD4+ (rCD4+) T cells isolated from people living with HIV on antiretroviral therapy, induction of ISR/ATF4 signaling reduced HIV reservoirs by depletion of replication-competent HIV without global reduction in the rCD4+ T cell population. These findings suggest that compromised ISR/ATF4 signaling maintains stable and quiescent HIV reservoirs whereas activation of ISR/ATF4 signaling results in the disruption of latent HIV and clearance of persistently infected CD4+T cells.