Isotretinoin promotes elimination of translation-competent HIV latent reservoirs in CD4T cells

Authors

J Natalie Howard, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America.
Callie Levinger, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America.
Selase Deletsu, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America.
Rémi Fromentin, Centre de recherche du CHUM et Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Canada.
Nicolas Chomont, Centre de recherche du CHUM et Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, Canada.
Alberto Bosque, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington DC, United States of America.

Document Type

Journal Article

Publication Date

10-1-2024

Journal

PLoS pathogens

Volume

20

Issue

10

DOI

10.1371/journal.ppat.1012601

Abstract

Development of novel therapeutic strategies that reactivate latent HIV and sensitize reactivated cells to apoptosis is crucial towards elimination of the latent viral reservoir. Among the clinically relevant latency reversing agents (LRA) under investigation, the γc-cytokine IL-15 and the superagonist N-803 have been shown to reactivate latent HIV ex vivo and in vivo. However, their clinical benefit can be hindered by IL-15 promoting survival of infected cells. We previously identified a small molecule, HODHBt, that sensitizes latently infected cells to death upon reactivation with γc-cytokines through a STAT-dependent pathway. In here, we aimed to identify and evaluate FDA-approved compounds that could also sensitize HIV-infected cells to apoptosis. Using the Connectivity Map (CMap), we identified the retinol derivative 13-cis-retinoic acid (Isotretinoin) causes similar transcriptional changes as HODHBt. Isotretinoin enhances IL-15-mediated latency reversal without inducing proliferation of memory CD4 T cells. Ex vivo analysis of PBMCs from ACTG A5325, where Isotretinoin was administered to ART-suppressed people with HIV, showed that Isotretinoin treatment enhances IL-15-mediated latency reversal. Furthermore, we showed that a combination of IL-15 with Isotretinoin promotes the reduction of translation-competent reservoirs ex vivo. Mechanistically, combination of IL-15 and Isotretinoin increases caspase-3 activation specifically in HIV-infected cells but not uninfected cells. Our results suggest that Isotretinoin can be a novel approach to target and eliminate translation-competent HIV reservoirs.

APA Citation

Howard, J Natalie; Levinger, Callie; Deletsu, Selase; Fromentin, Rémi; Chomont, Nicolas; and Bosque, Alberto, "Isotretinoin promotes elimination of translation-competent HIV latent reservoirs in CD4T cells" (2024). GW Authored Works. Paper 5840.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/5840

Department

Microbiology, Immunology, and Tropical Medicine