AUTHOR=Sanz Marta , Weideman Ann Marie K. , Ward Adam R. , Clohosey Matthew L. , Garcia-Recio Susana , Selitsky Sara R. , Mann Brendan T. , Iannone Marie Anne , Whitworth Chloe P. , Chitrakar Alisha , Garrido Carolina , Kirchherr Jennifer , Coffey Alisha R. , Tsai Yi- Hsuan , Samir Shahryar , Xu Yinyan , Copertino Dennis , Bosque Alberto , Jones Brad R. , Parker Joel S. , Hudgens Michael G. , Goonetilleke Nilu , Soriano-Sarabia Natalia TITLE=Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1 JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1219250 DOI=10.3389/fimmu.2023.1219250 ISSN=1664-3224 ABSTRACT=

Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.