Determinants of successful AAV-vectored delivery of HIV-1 bNAbs in early life

• 成果类型: Article
• 署名作者: Ardeshir, Amir; O'Hagan, Daniel; Mehta, Isha; Shandilya, Siddhartha; Hopkins, Lincoln L. J.; Adamson, Lourdes; Kuroda, Marcelo J.; Hahn, Patricia A.; da Costa, Lucas A. B.; Fuchs, Sebastian P.; Martinez-Navio, Jose M.; Gardner, Matthew R.; Van Rompay, Koen K. A.; Magnani, Diogo M.; Lifson, Jeffrey D.; Gao, Guangping; Farzan, Michael; Desrosiers, Ronald C.; Das, Jishnu; Martins, Mauricio A.
• 署名单位: University of California System; University of California Davis; State University System of Florida; University of Florida; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Miami; Emory University; Emory University; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; Tulane University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09330-2
• 发表日期: 2025-09-25
• 关键词: adenoassociated virus vector; neutralizing antibodies; t-cells; monoclonal-antibodies; gene-therapy; tolerance; responses; CHILDREN; transplantation; prevention

摘要

Despite advances in HIV-1 prophylaxis, vertical transmission remains a pressing problem in developing countries1. Given the promise of broadly neutralizing antibodies (bNAbs) for HIV-1 prevention2, we hypothesized that neonatal delivery of bNAbs using adeno-associated virus (AAV) could provide durable HIV-1 immunity during infancy. Here, using infant rhesus macaques (Macaca mulatta) as a model, we show that a one-time administration of an AAV vector encoding bNAb 3BNC117 at birth led to sustained bNAb expression for more than three years without redosing. This approach significantly protected both infant and pre-adolescent rhesus macaques from infection with simian-human immunodeficiency virus in mucosal challenge models that mimic HIV-1 transmission through breastfeeding and sexual intercourse. Age at the time of AAV-3BNC117 administration was a main determinant of success and was inversely correlated with the incidence of host anti-drug antibodies that restricted bNAb expression. Consistent with principles of neonatal tolerance3,4, newborn rhesus macaques exhibited higher levels of bNAb expression than older infants and juveniles following AAV-3BNC117 dosing. Furthermore, in utero exposure to recombinant 3BNC117 suppressed anti-drug antibodies and improved AAV-vectored delivery of this bNAb in older infants. Thus, our results suggest that neonatal and fetal immunological tolerance can be leveraged to improve postnatal AAV delivery of HIV-1 bNAbs in primates. Since years-long HIV-1 immunity can be generated in rhesus macaques from a one-time AAV vector administration at birth, future studies should evaluate the ability of this strategy to prevent perinatal and adolescent HIV-1 infections in humans.