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Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1.

Authors :
Sanz M
Weideman AMK
Ward AR
Clohosey ML
Garcia-Recio S
Selitsky SR
Mann BT
Iannone MA
Whitworth CP
Chitrakar A
Garrido C
Kirchherr J
Coffey AR
Tsai YH
Samir S
Xu Y
Copertino D
Bosque A
Jones BR
Parker JS
Hudgens MG
Goonetilleke N
Soriano-Sarabia N
Source :
BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 07. Date of Electronic Publication: 2023 Feb 07.
Publication Year :
2023

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.

Details

Language :
English
Database :
MEDLINE
Journal :
BioRxiv : the preprint server for biology
Accession number :
36798291
Full Text :
https://doi.org/10.1101/2023.02.07.527421