Awakening intracellular immunity for functional HIV cure

ABSTRACT HIV persists in long-lived CD4⁺ T cell reservoirs despite antiretroviral therapy (ART) 1 . Elite controllers suppress viraemia without ART 2 , yet reservoir reactivation emerges with immune ageing 3 . 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 4 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.