Modeling HIV infection, treatment, rebound, and intervention in human immune organoids

  • bioRxiv. 2026 Jan 27:2026.01.25.701611. doi: 10.64898/2026.01.25.701611.
Sarah A Sackey  1  2 ,  Jacob E Schrum  2 ,  Uma M Mangalanathan  2 ,  Rachel S Fish  3 ,  Elsa Sola  4 ,  Ahmad Selehi  5 ,  Ruoxi Pi  2 ,  Jerome A Zack  6  7 ,  Jocelyn T Kim  8 ,  Dara A Lehman  3 ,  Mark M Davis  1  4  9 ,  Catherine A Blish  1  2  10
Affiliations
  • 1. Stanford Immunology Program, Stanford University School of Medicine, Stanford, CA, USA.
  • 2. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • 3. Division of Human Biology, Fred Hutch Cancer Center, Seattle, WA, USA.
  • 4. Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA, USA.
  • 5. Donor Network West, San Ramon, California, USA.
  • 6. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA.
  • 7. Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, California, USA.
  • 8. Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, California, 90095, USA.
  • 9. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
  • 10. Chan Zuckerberg Biohub, San Francisco, CA, USA.
PMID: 41659627 DOI: 10.64898/2026.01.25.701611
Abstract

Targeting the HIV-infected reservoir in lymphoid tissues (LT) will be critical to developing a cure for people living with HIV (PLWH). LT explants used to study HIV Infection enable the evaluation of human-specific disease progression and treatment response; however, their short lifespan makes it challenging to assess long-term treatment interventions. We therefore established an immune Organoid model of HIV Infection using human tonsil or spleen cells, demonstrating productive HIV Infection and viral integration into CD4+ T cells. Treatment with a protease inhibitor fully suppressed ongoing viral production, with virologic rebound occurring within days of treatment interruption. The transfer of healthy allogeneic NK cells to target the reservoir upon treatment interruption reduced the number of infected cells, intact viral genomes, and production of de novo infectious viral particles. Adoption of this immune Organoid platform will accelerate the evaluation of cure-based strategies to eliminate the HIV reservoir in tissues for PLWH.

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