Transient reprogramming of CD4+ T cells through sestrin-MAPK complex disruption activates a RAG recombinase-mediated intracellular immunity pathway that eliminates integrated HIV DNA from patient-derived cells and tissue reservoirs independently of antiretroviral therapy, achieving durable functional cure in humanized mouse models through competitive displacement of HIV integrase from chromatin complexes.

HIV persists in long-lived CD4⁺ T cell reservoirs despite antiretroviral therapy (ART). Elite controllers suppress viraemia without ART, yet reservoir reactivation emerges with immune ageing. Here we show that transient reprogramming of patient-derived CD4⁺ T cells restores their ability to eliminate HIV-infected reservoirs, excising integrated proviral DNA. A defined compound, or physiological induction, drove rapid reprogramming ex vivo, enabling clearance of HIV DNA within hours to days of treatment, independently of ART. Single-cell RNA sequencing revealed activation of an antiviral telomere transfer programme that exceeds elite-like control. In humanised mice, adoptive transfer of reprogrammed patient CD4⁺ T cells, or in vivo reprogramming of murine T cells, eliminated HIV DNA across reservoirs, with undetectable viral genomes persisting for months. Modelling predicted that residual proviral reactivation would be governed by rare stochastic events, rendering viral rebound unlikely within a human lifespan. These findings identify a previously unrecognised form of intracellular immunity and establish a defined route to a functional HIV cure arising from the CD4⁺ T cell itself.