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

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Abstract

BACKGROUND. We performed 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 trial addressed the method of zinc finger nuclease (ZFN) ex vivo delivery, whether CCR5 Δ32 heterozygotes preferentially benefit, the effect of CCR5 gene edited CD4 T cells on the HIV-specific T cell response, and the ability of infused CCR5 gene edited T cells to delay viral rebound during analytical treatment interruption. We enrolled 14 people living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured time to viral rebound after ART withdrawal, 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. Modest delay to the time of viral rebound was observed relative to historical controls; however, three of 14 individuals of which two were CCR5 Δ32 heterozygotes appeared to regain control of viremia before ultimately rebounding. Interestingly, only these individuals had significant restoration of HIV-specific CD8 T cell responses. Immune escape to one of these re-invigorated responses was observed 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 pre-existing HIV-specific immune responses. TRIAL REGISTRATION. ClinicalTrials.gov NCT02388594 FUNDING. R01AI104400 (C.H.J.), UM1AI126620 (J.L.R.) funded by NIAID, NIDA, NIMH, and NINDS; T32 grant AI007632 (C.R.M.)

Authors

Pablo Tebas, Julie K. Jadlowsky, Pamela A. Shaw, Lifeng Tian, Erin Esparza, Andrea 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