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

Amir Ardeshir, Daniel O’Hagan, Isha Mehta, Siddhartha Shandilya, Lincoln L. J. Hopkins, Lourdes Adamson, Marcelo J. Kuroda, Patricia A. Hahn, Lucas A. B. Costa, Sebastian P. Fuchs, Jose M. Martinez-Navio, Matthew R. Gardner, Koen K. A. Rompay, Diogo M. Magnani, Jeffrey D. Lifson, Guangping Gao, Michael Farzan, Ronald C. Desrosiers, Jishnu Das and Mauricio A. Martins ()
Additional contact information
Amir Ardeshir: University of California, Davis
Daniel O’Hagan: University of Florida
Isha Mehta: University of Pittsburgh
Siddhartha Shandilya: University of Florida
Lincoln L. J. Hopkins: University of California, Davis
Lourdes Adamson: University of California, Davis
Marcelo J. Kuroda: University of California, Davis
Patricia A. Hahn: University of Florida
Lucas A. B. Costa: University of Florida
Sebastian P. Fuchs: University of Miami
Jose M. Martinez-Navio: University of Miami
Matthew R. Gardner: Emory University
Koen K. A. Rompay: University of California, Davis
Diogo M. Magnani: UMass Chan Medical School
Jeffrey D. Lifson: Frederick National Laboratory for Cancer Research
Guangping Gao: UMass Chan Medical School
Michael Farzan: University of Florida
Ronald C. Desrosiers: University of Miami
Jishnu Das: University of Pittsburgh
Mauricio A. Martins: University of Florida

Nature, 2025, vol. 645, issue 8082, 1020-1028

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-09330-2

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