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

作者：Sebastian Fuchs, P.G. Mondragon, Rachel Zabizhin, Shallu Tomer, Li Wang, E. Fullerton Cook, Dawn M. Dudley, Kimberly L. Weisgrau, Jessica Furlott, Jennifer Coonen, Eric T. Alexander, Jun Xie, Guangping Gao, James M. Termini, José M. Martinez-Navío, Anjie Zhen, Ronald C. Desrosiers · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-63970-6 · 被引用次数：7 · 研究领域：HIV Research and Treatment、Immune Cell Function and Interaction、Cytomegalovirus and herpesvirus research

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. A gene therapy method using AAV can help deliver HIV-fighting antibodies long-term, but the body often rejects them. Here the authors show that a short course of the drug rapamycin helps prevent host anti-drug antibody responses, showing successful antibody delivery in mice and monkeys.