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HIV-specific and resistant CAR T cells promote control of HIV replication in people with HIV
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In this first-in-human study, we evaluated autologous HIV-specific CARTs engineered to target HIV envelope via CD4 binding made resistant to HIV infection through CCR5 editing. Treatment was well tolerated, with no cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or other serious treatment-related adverse events. Although most participants experienced viral rebound during ATI, several exhibited evidence of post-rebound virologic control, including one participant (02) who maintained plasma HIV RNA below 1,000 copies mL−1 for more than 90 weeks without ART and another (06) who following rebound exhibited a rapid decline in viral load during the planned 16-week ATI. Moreover, in one participant (05), no rebound occurred during the ATI. These findings provide clinical evidence that HIV-specific, HIV-resistant CARTs can contribute to control of HIV replication following ART withdrawal.
Several limitations should be acknowledged. This was a small pilot study without a control arm and included only male participants. Participant-specific factors, including prior receipt of CCR5-edited CD4 T cells in participant 02 (participant 20525 and participant 3019), may also have influenced outcomes. Finally, most analyses were performed in peripheral blood and may not adequately reflect CART persistence or activity within lymphoid and mucosal tissues, where HIV persists. Together, these results demonstrate that HIV-specific, HIV-resistant CARTs can be safely administered to PWH and can exert measurable antiviral activity in vivo. The data support a model in which these cells contribute to viral control through both direct targeting of infected cells and enhancement of endogenous HIV-specific immunity. Future studies should focus on increasing the proportion of HIV-resistant CAR T cells, defining and perhaps promoting their tissue distribution and persistence, optimizing ATI timing, and evaluating combinations with broadly neutralizing antibodies, therapeutic vaccines, and latency-targeting interventions. As HIV cure strategies continue to evolve, HIV-specific CARTs may provide a durable cellular component capable of recognizing rebounding virus and maintaining long-term immune surveillance in the absence of ART.
https://pmc.ncbi.nlm.nih.gov/articles/PMC13345553/
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