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

Dajiang Li; Lilly M Wong; Yuyang Tang; Brigitte Allard; Katherine S James; George R Thompson; Satya Dandekar; Edward P Browne; Qingsheng Li; Jeremy M Simon; Nancie M Archin; David M Margolis; Guochun Jiang

doi:10.1016/j.isci.2022.105743

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

iScience. 2022 Dec 7;26(1):105743. doi: 10.1016/j.isci.2022.105743. eCollection 2023 Jan 20.

Authors

Dajiang Li¹, Lilly M Wong¹, Yuyang Tang¹, Brigitte Allard¹, Katherine S James¹, George R Thompson², Satya Dandekar², Edward P Browne^{1

3}, Qingsheng Li⁴, Jeremy M Simon⁵, Nancie M Archin¹, David M Margolis^{1

6

3}, Guochun Jiang^{1

7}

Affiliations

¹ UNC HIV Cure Center, Institute of Global Health and Infectious Diseases, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7042, USA.
² Department of Medical Microbiology, the University of California at Davis, Davis, CA 95616, USA.
³ Department of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7042, USA.
⁴ School of Biological Sciences and Nebraska Center for Virology, the University of Nebraska-Lincoln, Lincoln, NE 68588-0118, USA.
⁵ Department of Genetics, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7042, USA.
⁶ Department of Microbiology and Immunology, UNC Neuroscience Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7042, USA.
⁷ Department of Biochemistry and Biophysics, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7042, USA.

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.

Keywords: Immunology; Transcriptomics; Virology.

Abstract

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