Transient rapamycin treatment avoids unwanted host immune responses toward AAV-delivered anti-HIV antibodies

  • Nat Commun. 2025 Oct 7;16(1):8906. doi: 10.1038/s41467-025-63970-6.
Sebastian P Fuchs  1 ,  Paula G Mondragon  1 ,  Rachel Zabizhin  1 ,  Shallu Tomer  2 ,  Li Wang  2 ,  Ethan Cook  2 ,  Dawn M Dudley  3 ,  Kimberly L Weisgrau  3 ,  Jessica Furlott  3 ,  Jennifer Coonen  3 ,  Eric Alexander  3 ,  Jun Xie  4 ,  Guangping Gao  4 ,  James M Termini  1 ,  Jose M Martinez-Navio  1 ,  Anjie Zhen  5 ,  Ronald C Desrosiers  6
Affiliations
  • 1. Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 2. Department of Hematology/Oncology, University of California-Los Angeles, Los Angeles, CA, USA.
  • 3. Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA.
  • 4. Department of Genetics & Cellular Medicine, Horae Gene Therapy Center, UMass Chan Medical School, Worcester, MA, USA.
  • 5. Department of Hematology/Oncology, University of California-Los Angeles, Los Angeles, CA, USA. [email protected].
  • 6. Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA. [email protected].
PMID: 41057323 DOI: 10.1038/s41467-025-63970-6
Abstract

Long-term delivery of broadly neutralizing antibodies (bnAbs) using adeno-associated virus (AAV) vector is a promising approach for both the prevention and treatment of HIV Infection. However, host anti-drug antibody (ADA) responses severely limit the continuous delivery of these anti-HIV bnAbs and have been the most important obstacle for development of this approach for widespread human use. Transient treatment with the immunomodulatory agent rapamycin (sirolimus) allows for continuous long-term delivery of the anti-HIV bnAb 3BNC117 in immunocompetent mice in the absence of detectable ADAs. Use of the agent in monkeys results in 12 of 15 successful deliveries of the bnAbs 3BNC117, 10-1074, and PGT145 following drug cessation across all Animals. The results of this 5-monkey trial lend strong support to continuing studies in SHIV-infected monkeys and use of this approach in humans for potential worldwide use.

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