Transient CD4+ T cell depletion during suppressive ART reduces the HIV reservoir in humanized mice

• Type of Material: Article
• Authors: Lijun Ling, University of North Carolina, Chapel Hill; Chandrav De, University of North Carolina, Chapel Hill; Rae Ann Sapgnuolo, University of North Carolina, Chapel Hill; Nurjahan Begum, University of North Carolina, Chapel Hill; Shane D. Falcinelli, University of North Carolina, Chapel Hill; Nancie M. Archin, University of North Carolina, Chapel Hill; Martina Kovarova, University of North Carolina, Chapel Hill; Guido Silvestri, Emory University; Angela Wahl, University of North Carolina, Chapel Hill; David M. Margolis, University of North Carolina, Chapel Hill; J. Victor Garcia, University of North Carolina, Chapel Hill
• Language: English
• Date: 2023-12-06
• Publisher: PLOS
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Ling et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1371/journal.ppat.1011824
• Title of Journal or Parent Work: PLOS Pathogens
• Volume: 19
• Issue: 12
• Start Page: e1011824
• Grant/Funding Information: This work was supported by funding from National Institutes of Health grants UM1-AI-164567 (D,M.M.), P30AI050410 (D,M.M.), F30 AI145588 (S.D.F.).
• Keywords: antiretroviral therapy; humanized mice; HIV; Lifelong treatment
• Research Categories: Biology, Virology; Health Sciences, Pharmacology; Health Sciences, Immunology

Abstract

Lifelong treatment is required for people living with HIV as current antiretroviral therapy (ART) does not eradicate HIV infection. Latently infected cells are essentially indistinguishable from uninfected cells and cannot be depleted by currently available approaches. This study evaluated antibody mediated transient CD4+ T cell depletion as a strategy to reduce the latent HIV reservoir. Anti-CD4 antibodies effectively depleted CD4+ T cells in the peripheral blood and tissues of humanized mice. We then demonstrate that antibody-mediated CD4+ T cell depletion of HIV infected ART-suppressed animals results in substantial reductions in cell-associated viral RNA and DNA levels in peripheral blood cells over the course of anti-CD4 antibody treatment. Recovery of CD4+ T cells was observed in all tissues analyzed except for the lung 26 days after cessation of antibody treatment. After CD4+ T cell recovery, significantly lower levels of cell-associated viral RNA and DNA were detected in the tissues of anti-CD4 antibody-treated animals. Further, an 8.5-fold reduction in the levels of intact HIV proviral DNA and a 3.1-fold reduction in the number of latently infected cells were observed in anti-CD4-antibody-treated animals compared with controls. However, there was no delay in viral rebound when ART was discontinued in anti-CD4 antibody-treated animals following CD4+ T cell recovery compared with controls. Our results suggest that transient CD4+ T cell depletion, a long-standing clinical intervention that might have an acceptable safety profile, during suppressive ART can reduce the size of the HIV reservoir in humanized mice.