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

Author

Listed:
  • Sebastian P. Fuchs

    (University of Miami)

  • Paula G. Mondragon

    (University of Miami)

  • Rachel Zabizhin

    (University of Miami)

  • Shallu Tomer

    (University of California—Los Angeles)

  • Li Wang

    (University of California—Los Angeles)

  • Ethan Cook

    (University of California—Los Angeles)

  • Dawn M. Dudley

    (University of Wisconsin)

  • Kimberly L. Weisgrau

    (University of Wisconsin)

  • Jessica Furlott

    (University of Wisconsin)

  • Jennifer Coonen

    (University of Wisconsin)

  • Eric Alexander

    (University of Wisconsin)

  • Jun Xie

    (UMass Chan Medical School)

  • Guangping Gao

    (UMass Chan Medical School)

  • James M. Termini

    (University of Miami)

  • Jose M. Martinez-Navio

    (University of Miami)

  • Anjie Zhen

    (University of California—Los Angeles)

  • Ronald C. Desrosiers

    (University of Miami)

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.

Suggested Citation

  • Sebastian P. Fuchs & Paula G. Mondragon & Rachel Zabizhin & Shallu Tomer & Li Wang & Ethan Cook & Dawn M. Dudley & Kimberly L. Weisgrau & Jessica Furlott & Jennifer Coonen & Eric Alexander & Jun Xie &, 2025. "Transient rapamycin treatment avoids unwanted host immune responses toward AAV-delivered anti-HIV antibodies," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63970-6
    DOI: 10.1038/s41467-025-63970-6
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    1. Sung-Youl Ko & Amarendra Pegu & Rebecca S. Rudicell & Zhi-yong Yang & M. Gordon Joyce & Xuejun Chen & Keyun Wang & Saran Bao & Thomas D. Kraemer & Timo Rath & Ming Zeng & Stephen D. Schmidt & John-Pau, 2014. "Enhanced neonatal Fc receptor function improves protection against primate SHIV infection," Nature, Nature, vol. 514(7524), pages 642-645, October.
    2. Amine Meliani & Florence Boisgerault & Romain Hardet & Solenne Marmier & Fanny Collaud & Giuseppe Ronzitti & Christian Leborgne & Helena Costa Verdera & Marcelo Simon Sola & Severine Charles & Alban V, 2018. "Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    3. Matthew R. Gardner & Lisa M. Kattenhorn & Hema R. Kondur & Markus von Schaewen & Tatyana Dorfman & Jessica J. Chiang & Kevin G. Haworth & Julie M. Decker & Michael D. Alpert & Charles C. Bailey & Erne, 2015. "AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges," Nature, Nature, vol. 519(7541), pages 87-91, March.
    4. Laura M. Walker & Michael Huber & Katie J. Doores & Emilia Falkowska & Robert Pejchal & Jean-Philippe Julien & Sheng-Kai Wang & Alejandra Ramos & Po-Ying Chan-Hui & Matthew Moyle & Jennifer L. Mitcham, 2011. "Broad neutralization coverage of HIV by multiple highly potent antibodies," Nature, Nature, vol. 477(7365), pages 466-470, September.
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