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

Frontiers in Immunology

Immunology

Ann Marie K. Weideman¹  Michael G. Hudgens¹  Dennis Copertino²  Brendan T. Mann³  Marta Sanz³  Natalia Soriano-Sarabia³  Alisha Chitrakar³  Alberto Bosque³  Adam R. Ward⁴  Brad R. Jones⁴  Marie Anne Iannone⁵  Yi- Hsuan Tsai⁵  Alisha R. Coffey⁵  Joel S. Parker⁶  Susana Garcia-Recio⁶  Sara R. Selitsky⁶  Nilu Goonetilleke⁷  Yinyan Xu⁷  Shahryar Samir⁷  Carolina Garrido⁸  Chloe P. Whitworth⁸  Jennifer Kirchherr⁸  Matthew L. Clohosey⁸ 

[1] Biostatistics Core, Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States;Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States;Department of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States;Department of Microbiology Immunology and Tropical Medicine, the George Washington University, Washington, DC, United States;Department of Microbiology Immunology and Tropical Medicine, the George Washington University, Washington, DC, United States;Department of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States;Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States;Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States;Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States;UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States;

关键词: HIV cure;    latency reversing agents;    shock and kill;    IPDA;    gamma delta (γδ) T cells;    aminobisphosphonates;   

DOI  :  10.3389/fimmu.2023.1219250

 received in 2023-05-08, accepted in 2023-08-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Sanz, Weideman, Ward, Clohosey, Garcia-Recio, Selitsky, Mann, Iannone, Whitworth, Chitrakar, Garrido, Kirchherr, Coffey, Tsai, Samir, Xu, Copertino, Bosque, Jones, Parker, Hudgens, Goonetilleke and Soriano-Sarabia