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CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication
Pablo Tebas, … , Carl H. June, James L. Riley
Pablo Tebas, … , Carl H. June, James L. Riley
Published February 11, 2021
Citation Information: J Clin Invest. 2021;131(7):e144486. https://doi.org/10.1172/JCI144486.
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Clinical Research and Public Health AIDS/HIV

CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication

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Abstract

Background We conducted a phase I clinical trial that infused CCR5 gene–edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies.Methods The aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene–edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene–edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response.Results Infusion of the CD4+ T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Δ32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8+ T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8+ T cell responses.Conclusion These findings demonstrate how CCR5 gene–edited CD4+ T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses.REGISTRATION ClinicalTrials.gov NCT02388594.Funding NIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.

Authors

Pablo Tebas, Julie K. Jadlowsky, Pamela A. Shaw, Lifeng Tian, Erin Esparza, Andrea L. Brennan, Sukyung Kim, Soe Yu Naing, Max W. Richardson, Ashley N. Vogel, Colby R. Maldini, Hong Kong, Xiaojun Liu, Simon F. Lacey, Anya M. Bauer, Felicity Mampe, Lee P. Richman, Gary Lee, Dale Ando, Bruce L. Levine, David L. Porter, Yangbing Zhao, Don L. Siegel, Katharine J. Bar, Carl H. June, James L. Riley

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Figure 1

Schematic outlining the timeline and sample collection points for NCT02388594.

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Schematic outlining the timeline and sample collection points for NCT023...
The clinical study was divided into 4 steps. During step 1, participants underwent leukapheresis to collect cells for manufacturing, followed by a second leukapheresis and rectal biopsy to serve as baseline samples. In cohorts 2 and 3, participants were treated with a single dose of cyclophosphamide 2 days before receiving modified cells (day –2). Participants entered step 2 on the day of cell infusion (day 0), and the edited cells were allowed to engraft for either 4 weeks (cohorts 2 and 3) or 8 weeks (cohort 1) before the 16-week analytical treatment interruption was initiated in step 3. At the conclusion of the treatment interruption, the participants entered step 4 to be monitored for safety until HIV RNA levels fell below the limit of quantification. Safety laboratory values and HIV viral load were monitored at regular intervals throughout the study.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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