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

Authors

• 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.

APA Citation

Sanz, Marta; Weideman, Ann Marie; 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; and Soriano-Sarabia, Natalia, "Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1" (2023). GW Authored Works. Paper 3440.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3440

Department

Microbiology, Immunology, and Tropical Medicine