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

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Creator
  • Sanz M.
    • Other Affiliation: George Washington University
  • Weideman A.M.K.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Ward A.R.
    • Other Affiliation: George Washington University
  • Clohosey M.L.
    • Affiliation: HIV Cure Center
  • Garcia-Recio S.
    • Affiliation: School of Medicine, Department of Genetics
  • Selitsky S.R.
    • Affiliation: School of Medicine, Department of Genetics
  • Mann B.T.
    • Other Affiliation: George Washington University
  • Iannone M.A.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Whitworth C.P.
    • Affiliation: HIV Cure Center
  • Chitrakar A.
    • Other Affiliation: George Washington University
  • Garrido C.
    • Affiliation: HIV Cure Center
  • Kirchherr J.
    • Affiliation: HIV Cure Center
  • Coffey A.R.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Tsai Y.H.
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Samir S.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Xu Y.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Copertino D.
    • Other Affiliation: Weill Cornell Medicine
  • Bosque A.
    • Other Affiliation: George Washington University
  • Jones B.R.
    • Other Affiliation: George Washington University
  • Parker J.S.
    • Affiliation: School of Medicine, Department of Genetics
  • Hudgens M.G.
    • Affiliation: Gillings School of Global Public Health, Department of Biostatistics
  • Goonetilleke N.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • Soriano-Sarabia N.
    • Other Affiliation: George Washington University
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.
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  • Article
License
  • Attribution 4.0 International
Journal title
  • Frontiers in Immunology
Journal volume
  • 14
Language
  • English
Version
  • Publisher
Funder
  • University of North Carolina, UNC
  • National Institutes of Health, NIH, (R01AI125097, R21AI157864, UM1 AI126619)
  • UNC Center for Mental Health and Susceptibility, (P30ES010126, UM1 AI106701, UM1AI068634, UM1AI068636)
  • Center for AIDS Research, University of North Carolina at Chapel Hill, UNC CFAR, (P30AI050410)
  • District of Columbia Developmental Center for AIDS Research, DC D-CFAR, (P30AU117970)
  • National Institute of Allergy and Infectious Diseases, NIAID
  • University Cancer Research Fund, (30CA016086)
ISSN
  • 1664-3224
Publisher
  • Frontiers Media SA

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