Depletion of HIV reservoir by activation of ISR signaling in resting CD4⁺T cells

Authors

Dajiang Li, University of North Carolina at Chapel Hill
Lilly M. Wong, University of North Carolina at Chapel Hill
Yuyang Tang, University of North Carolina at Chapel Hill
Brigitte Allard, University of North Carolina at Chapel Hill
Katherine S. James, University of North Carolina at Chapel Hill
George R. Thompson, the University of California at Davis,
Satya Dandekar, the University of California at Davis,
Edward P. Browne, University of North Carolina at Chapel Hill
Qingsheng Li, University of Nebraska - LincolnFollow
Jeremy M. Simon, University of North Carolina at Chapel Hill
Nancie M. Archin, University of North Carolina at Chapel Hill
David M. Margolis, University of North Carolina at Chapel Hill
Guochun Jiang, University of North Carolina at Chapel Hill

Document Type

Article

Date of this Version

1-20-2023

Citation

Li et al., iScience 26, 105743 January 20, 2023 © 2022 The Author(s). https://doi.org/10.1016/ j.isci.2022.105743

Comments

Open access.

Abstract

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.