Dynamic antigen expression and cytotoxic T cell resistance in HIV reservoir clones PMID: 41735521

ADC Targets in Oncology

2026-04-10

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

Nature. 2026 May;653(8115):850-860. doi: 10.1038/s41586-026-10298-w.

Isabella A T M Ferreira ^# ¹ ² , Alberto Herrera ^# ¹ ² ³ , Tan Thinh Huynh ¹ ² , Emily Stone ¹ ² , Noemi L Linden ¹ ² ³ , Cristian Ovies ¹ ² ³ , Yanqin Ren ¹ ² , Cintia Bittar ⁴ , Virender K Pal ⁵ , Ethan Naing ¹ ² , Parul Sinha ¹ ² , Ali Danesh ¹ ² , Eva Stevenson ¹ ² , Shane Vedova ¹ ² ³ , Fitty Liu ¹ ² ³ , Louise Leyre ¹ ² ³ , Skylar Shea ¹ ² , Elina Wells ¹ ² ³ , Itzayana G Miller ¹ ² ³ , Marie Canis ⁵ , Ana Rafaela Teixeira ⁴ , Susan Moir ⁶ , Tae-Wook Chun ⁶ , Colin Kovacs ⁷ , Madeleine S Gastonguay ⁸ , Alison L Hill ⁸ ⁹ , Shy Genel ¹⁰ , Paul Zumbo ¹¹ , Doron Betel ¹¹ ¹² ¹³ , Elias K Halvas ¹⁴ , Guinevere Q Lee ¹ ² , Rachel Scheck ¹ ² , Marina Caskey ⁴ , Paul D Bieniasz ⁵ ¹⁵ , Nathan L Board ¹ ² , Michel C Nussenzweig ⁴ ¹⁵ , R Brad Jones ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1. Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
2. Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
3. Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, NY, USA.
4. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA.
5. Laboratory of Retrovirology, The Rockefeller University, New York, NY, USA.
6. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
7. Maple Leaf Medical Clinic and Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
8. Institute for Computational Medicine and the Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
9. Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, Ontario, Canada.
10. Center for Computational Astrophysics, Flatiron Institute, New York, NY, USA.
11. Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA.
12. Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
13. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA.
14. Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
15. Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
16. Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY, USA. [email protected].
17. Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA. [email protected].
18. Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, NY, USA. [email protected].
19. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA. [email protected].
# Contributed equally.

Abstract

Clonally expanded CD4⁺ T cells harbouring rebound-competent HIV persist lifelong during antiretroviral therapy^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-harbouring cells, implicating prosurvival 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 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.