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

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. Author summary: Even with the development and rapid advancement of antiretroviral therapies (ART) against HIV in the past three decades, there is still no generalized cure for HIV. Identification of novel therapeutic interventions that target the latent reservoir could provide new avenues to find a cure. In this work, we evaluated the ability of the FDA-approved compound Isotretinoin to reactivate latent HIV and promote a reduction of the latent reservoir ex vivo. Our studies found that Isotretinoin can enhance the ability of IL-15 to reactivate latent reservoirs. Furthermore, using samples from clinical trial ACTG A5325 (NCT01969058) we show that Isotretinoin sensitizes latent HIV to reactivation by IL-15. Finally, we demonstrate that Isotretinoin can sensitize reactivated cells to death via apoptosis. Overall, this study demonstrate that Isotretinoin could be used in combinatorial strategies towards the development of an HIV cure to promote reduction of latent reservoirs. [ABSTRACT FROM AUTHOR]