Dynamic antigen expression and cytotoxic T cell resistance in HIV reservoir clones

Abstract

Clonally expanded CD4⁺ T-cells harboring rebound-competent HIV persist lifelong during ART^1-5. Latency is considered the principal barrier to viral eradication and has resisted pharmacological reversal^6,7, yet sustained immune pressure appears to erode reservoirs^8-15. Recent advances have yielded glimpses into exceptionally rare reservoir-harboring cells, implicating pro-survival properties in persistence^16-18. 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.