Clonally expanded CD4+ T cells harbouring rebound-competent HIV persist lifelong during antiretroviral therapy1–5. Latency is considered the principal barrier to viral eradication and has resisted pharmacological reversal6,7, yet sustained immune pressure appears to erode reservoirs8–15. Recent advances have yielded glimpses into exceptionally rare reservoir-harbouring cells, implicating prosurvival properties in persistence16–18. Here we isolate and characterize authentic reservoir clones (ARCs) that robustly proliferate and accumulate while producing infectious virus, without overtly succumbing to cytopathicity. At any moment, only small fractions of ARCs expressed HIV proteins, a state associated with conserved host transcriptional programs but remarkably refractory to potent T cell stimulation. Nevertheless, sustained co-culture with a CD8+ cytotoxic T lymphocyte clone substantially culled proliferating ARCs, revealing time-integrated vulnerability to immune pressure. The corresponding ex vivo CD8+ T cell response was poorly cytotoxic, and in vivo erosion of ARCs occurred only slowly. A regulatory T cell ARC displayed pronounced cell-intrinsic resistance to cytotoxic T cells — a longstanding hypothesis now directly demonstrated — linked to low oxidative stress and reversed with deferoxamine19, a hypoxic stress inducer and FDA-approved therapeutic. Overall, we provide insights into the vulnerabilities of reservoir clones to potent, sustained cytotoxic T cell pressure and highlight intrinsic resistance pathways as actionable therapeutic targets, opening opportunities for advancing immune-based HIV cure strategies.
