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

Marta Sanz, Department of Microbiology Immunology and Tropical Medicine, the George Washington University, Washington, DC, United States.
Ann Marie Weideman, Biostatistics Core, Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Adam R. Ward, Department of Microbiology Immunology and Tropical Medicine, the George Washington University, Washington, DC, United States.
Matthew L. Clohosey, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Susana Garcia-Recio, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Sara R. Selitsky, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Brendan T. Mann, Department of Microbiology Immunology and Tropical Medicine, the George Washington University, Washington, DC, United States.
Marie Anne Iannone, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Chloe P. Whitworth, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Alisha Chitrakar, Department of Microbiology Immunology and Tropical Medicine, the George Washington University, Washington, DC, United States.
Carolina Garrido, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Jennifer Kirchherr, UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Alisha R. Coffey, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Yi-Hsuan Tsai, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Shahryar Samir, Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Yinyan Xu, Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Dennis Copertino, Department of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States.
Alberto Bosque, Department of Microbiology Immunology and Tropical Medicine, the George Washington University, Washington, DC, United States.
Brad R. Jones, Department of Microbiology Immunology and Tropical Medicine, the George Washington University, Washington, DC, United States.
Joel S. Parker, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Michael G. Hudgens, Biostatistics Core, Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Nilu Goonetilleke, Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Natalia Soriano-Sarabia, Department of Microbiology Immunology and Tropical Medicine, the George Washington University, Washington, DC, United States.

Document Type

Journal Article

Publication Date

1-1-2023

Journal

Frontiers in immunology

Volume

14

DOI

10.3389/fimmu.2023.1219250

Keywords

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

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 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.

Department

Microbiology, Immunology, and Tropical Medicine

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