Abstract Antiretroviral therapy (ART) fails to fully restore immune function and is not curative. A single infusion of CCR5 gene-edited autologous CD4 + T cells (SB-728-T) led to sustained increases in CD4 + T cell counts, improved T cell homeostasis, and reduced the estimated size of the HIV reservoir. These outcomes were associated with the expansion and long-term persistence of a novel CCR5 gene-edited CD4 + T memory stem cell (CD45RA int RO int T SCM ) subset that can replenish the pool of more differentiated memory cells. We showed that novel CD45RA int RO int T SCM cells are transcriptionally distinct from the previously described CD45RA + T SCM and are minimally differentiated cells uncommitted to a specific Th-lineage. Subsequently, we showed in an independent trial that infusion of the SB-728-T cell product resulted in partial control of viral replication upon cessation of ART which was correlated with the frequencies of CCR5 gene-edited T SCM and their T EM progeny. Interestingly, one participant that remained off ART to this date demonstrated long-term maintenance of CCR5 gene-edited cells and increased frequency of polyfunctional HIV-specific CD4 + and CD8 + T cells, contributing to low levels of viral load 5 years post-infusion. Consequently, the generation of HIV protected memory CD4 + T cells by CCR5 disruption can contribute toward novel interventions aimed at achieving a sustained ART-free viral remission of HIV disease.

Infusion of CCR5 Gene-Edited T Cells Allows Immune Reconstitution, HIV Reservoir Decay, and Long-Term Virological Control