- Isabella A. T. M. Ferreira1,2 na1,
- Alberto Herrera ORCID: orcid.org/0000-0003-4189-90511,2,3,16 na1,
- Tan Thinh Huynh ORCID: orcid.org/0009-0009-0286-39461,2,
- Emily Stone1,2,
- Noemi L. Linden ORCID: orcid.org/0000-0001-5035-67161,2,3,16,
- Cristian Ovies1,2,3,16,
- Yanqin Ren1,2,
- Cintia Bittar4,
- Virender K. Pal5,
- Ethan Naing1,2,
- Parul Sinha ORCID: orcid.org/0009-0002-2372-14871,2,
- Ali Danesh1,2,
- Eva Stevenson1,2,
- Shane Vedova1,2,3,16,
- Fitty Liu1,2,
- Louise Leyre1,2,3,16,
- Skylar Shea1,2,
- Elina Wells1,2,3,16,
- Itzayana G. Miller ORCID: orcid.org/0000-0001-9199-89851,2,3,16,
- Marie Canis5,
- Ana Rafaela Teixeira ORCID: orcid.org/0000-0003-1906-01024,
- Susan Moir6,
- Tae-Wook Chun ORCID: orcid.org/0000-0001-5153-73406,
- Colin Kovacs7,
- Madeleine S. Gastonguay ORCID: orcid.org/0000-0002-5700-85438,
- Alison L. Hill ORCID: orcid.org/0000-0002-6583-36238,9,
- Shy Genel10,
- Paul Zumbo11,
- Doron Betel ORCID: orcid.org/0000-0002-8006-775211,12,13,
- Elias K. Halvas14,
- Guinevere Q. Lee ORCID: orcid.org/0000-0002-9412-886X1,2,
- Rachel Scheck ORCID: orcid.org/0009-0004-8354-99431,2,
- Marina Caskey ORCID: orcid.org/0000-0003-1727-86934,
- Paul D. Bieniasz ORCID: orcid.org/0000-0002-2368-37195,15,
- Nathan L. Board ORCID: orcid.org/0000-0002-5208-99701,2,
- Michel C. Nussenzweig ORCID: orcid.org/0000-0003-0592-85644,15 &
- R. Brad Jones ORCID: orcid.org/0000-0003-4470-12311,2,3,16
Nature (2026)Cite this article
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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
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.
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