Clonally expanded CD4+ T-cells harboring rebound-competent HIV persist lifelong during ART1-5. 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-harboring cells, implicating pro-survival 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 CTL-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 novel insights into the vulnerabilities of reservoir clones to potent, sustained CTL pressure and highlight intrinsic resistance pathways as actionable therapeutic targets, opening opportunities for advancing immune-based HIV cure strategies.

Main-group catalysts that mimic transition metal reactivity can expand substrate tolerance and enable transformations not possible at present with metal catalysis1. The discovery that PIII and PV phosphorus intermediates can undergo transition-metal-like two-electron chemistry raises the question of whether radical PIV intermediates can mimic other elementary steps in organometallic chemistry2,3. Here we describe a phosphine-photoredox catalyst system that promotes intermolecular Markovnikov hydroamination of unactivated terminal alkenes with numerous classes of N-H azoles, a reaction that is not possible with late transition metal catalysis. Experimental and computational mechanistic studies support a new elementary step for main-group catalysis, in which a phosphine radical cation activates the alkene to nucleophilic amination by the azole, a step otherwise associated with transition metals. Given the broad value of nucleophilic alkene functionalization in transition metal catalysis, this PIV mechanism could offer new opportunities for main-group element catalysis and chemical synthesis.