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

After 30 years of failed attempts to deliver HIV antibodies via gene therapy, we discovered the solution was timing—specifically, the unique immune tolerance window in early life.

Our study (published in Nature) demonstrates that a single AAV vector injection encoding HIV broadly neutralizing antibody (bNAb) 3BNC117 provides protection for over three years when administered to newborn macaques. Success rates were striking: 89% in newborns versus only 33% in 2-year-olds. The key? Neonatal immune systems tolerate the introduced antibody, avoiding the anti-drug responses that have plagued adult gene therapy attempts.

This early-life window extends to approximately 4 weeks of age, with success declining progressively thereafter. We also showed that prenatal exposure to the antibody can extend this tolerance window, enabling successful gene therapy even in older infants. Most critically, treated infants maintained protective antibody levels through adolescence—covering the entire breastfeeding period and beyond with a single injection.

This breakthrough leverages fundamental immunological principles established 70 years ago, adapting them for modern gene therapy applications. For the 100,000+ babies who acquire HIV annually, predominantly in resource-limited settings, this one-shot approach could transform prevention strategies where maintaining regular medical care remains challenging.

https://doi.org/10.1038/s41586-025-09330-2