In a groundbreaking advancement poised to transform the landscape of HIV prevention, researchers at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology in Jupiter, Florida, have unveiled a novel gene therapy approach that could offer long-lasting protection against HIV-1 infection in newborns. This innovative strategy utilizes adeno-associated virus (AAV) vectors to deliver broadly neutralizing antibodies (bNAbs) directly to infants at birth, providing sustained immunity that might span several years with just a single administration. This breakthrough, published in the prestigious journal Nature, signals a monumental leap forward in combating mother-to-child transmission of HIV, particularly in resource-constrained regions where existing antiretroviral protocols face significant logistical challenges.
The clinical relevance of this study is underscored by the persistent global burden of pediatric HIV infections. Despite the widespread availability of antiretroviral therapies (ART) in developed nations, sub-Saharan Africa still accounts for the majority of new childhood HIV infections annually. Traditional prevention methods often demand strict medication adherence from both mothers and infants, a requirement that is difficult to meet in many settings due to healthcare infrastructure deficits and social determinants. This new approach, as articulated by lead author Dr. Mauricio Martins, an associate professor in the department of immunology and microbiology, offers a compelling alternative—one that circumvents the need for repeated dosing by administering a single gene therapy injection at birth.
Harnessing the power of AAV as a delivery vehicle, the research team engineered vectors encoding the genetic blueprint for 3BNC117, a potent broadly neutralizing antibody first isolated by Dr. Michel Nussenzweig’s lab at The Rockefeller University. Broadly neutralizing antibodies have the remarkable capacity to recognize and neutralize a diverse array of HIV-1 strains by targeting conserved viral epitopes, thus circumventing the virus’s notorious genetic variability. The underlying mechanism of action involves transducing host muscle cells to serve as endogenous factories for continuous antibody production, effectively immunizing the host against subsequent viral exposure without the need for external antibody administration.
This gene therapy was evaluated in a primate model utilizing newborn rhesus macaques, which mimic human infant immunity and HIV transmission through breastfeeding. The study’s findings were remarkable: nearly 90% of newborn macaques exhibited robust expression levels of 3BNC117 following a single intramuscular injection. More importantly, when challenged with simian-HIV via oral exposure that simulated breastfeeding transmission, the vast majority of treated neonates were protected from infection. This protective effect endured for multiple years, extending into adolescence, underscoring the potential durability of this intervention.
A critical observation was the diminished efficacy of the gene therapy when administered to older infant macaques, which opens an intriguing discussion about the developmental immunology shaping therapeutic outcomes. Neonatal immune systems appear uniquely receptive to AAV-mediated gene transfer, perhaps due to differences in muscle cell turnover, immune tolerance, or receptor expression. This finding advocates for early intervention at birth to optimize therapeutic benefit, aligning with public health goals to enact preventive strategies during the highest risk windows.
Safety considerations were equally promising. Throughout the extensive monitoring period, the researchers detected no adverse effects attributable to the gene therapy. This safety profile is pivotal for translating such therapies to human infants, where any risk-benefit imbalance must be meticulously evaluated. Furthermore, the viral vector system’s inherent stability and minimal cold chain requirements propose an ideal solution for deployment in remote or low-resource environments, where refrigeration infrastructure is limited or unreliable.
The investigation also explored maternal antibody influence, discovering that offspring born to mothers exposed to the bNAb gene therapy during pregnancy exhibited enhanced immunological tolerance, avoiding the immune rejection responses that can undermine effectiveness in other contexts. This phenomenon suggests maternal-fetal transfer of immune factors might prime the neonate for better acceptance of the transgene product, an aspect warranting deeper mechanistic studies to optimize maternal and infant interventions synergistically.
Beyond the immediate biomedical implications, this research heralds a paradigm shift in infectious disease prevention by leveraging in vivo gene delivery to establish passive immunity durably. Unlike conventional vaccines that stimulate active immune responses, gene therapy vector-mediated antibody expression bypasses the need for immune system priming and memory generation, directly supplying protective proteins. This approach is particularly advantageous for populations with immature or compromised immune systems, such as neonates born into HIV-endemic areas.
While these preclinical findings are exceptionally encouraging, the path forward includes rigorous clinical trials in human infants to validate safety, dosing parameters, and long-term efficacy. According to Dr. Martins, securing funding and support from global health organizations and philanthropic foundations is vital to translating this technology from bench to bedside. The impact potential is immense, offering the prospect of drastically reducing pediatric HIV infection rates and improving outcomes in some of the world’s most vulnerable communities.
This research also catalyzes broader possibilities for gene therapy in infectious diseases, expanding beyond HIV to other pathogens where antibody-mediated neutralization could confer protective advantage. The fusion of advanced molecular engineering with practical delivery systems exemplifies a new frontier in therapeutic innovation—one that integrates biological precision with real-world applicability.
Ultimately, the single-dose, lifelong protection concept epitomizes a major stride in preventative medicine, particularly in HIV—a disease where obstacles to adherence and access impede conventional therapies. The Wertheim UF Scripps Institute study exemplifies multidisciplinary collaboration, harnessing gene therapy, immunology, and virology to tackle one of the most pressing global health challenges. As this field evolves, its success will depend on continuing scientific rigor, ethical clinical development, and equitable distribution worldwide.
The vision articulated by the research team—an HIV intervention administered once at birth, providing enduring protection without recurring dosing—could redefine global HIV prevention strategies, particularly for newborns at risk through breastfeeding. This elegant solution may circumvent the logistical complexities of current ART regimens while empowering healthcare systems in underserved areas to better protect their youngest and most vulnerable members. While challenges remain ahead, the promise of this gene therapy approach fuels hope for a future where mother-to-child transmission of HIV can be virtually eliminated.
Subject of Research: Animals
Article Title: Determinants of successful AAV-vectored delivery of HIV-1 bNAbs in early life
News Publication Date: 30-Jul-2025
Web References:
References:
Martins, M.A., et al. (2025). Determinants of successful AAV-vectored delivery of HIV-1 bNAbs in early life. Nature. DOI: 10.1038/s41586-025-09330-2
Image Credits: Stacey DeLoye
Keywords: HIV prevention, Gene therapy
