Every year, over 100,000 children become infected with HIV – many within the first weeks or months of life, especially in sub-Saharan Africa. The global health community has made significant strides in reducing mother-to-child transmission, but barriers like limited access to antiretroviral therapy (ART), social inequities, and drug resistance continue to undermine progress. A recent study led by Mauricio A. Martins, Department of Immunology and Microbiology, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, proposes a gene therapy dosed at birth that could protect children from HIV for years.
The study notes that “rhesus macaques can develop durable HIV-1 bNAb immunity after receiving a single intramuscular dose of AAV-bNAb vectors at birth. Critically, as the monkeys matured from infancy into adolescence, the AAV-encoded IgG molecules continued to be produced in vivo and retained their antiviral functions, successfully blocking SHIV infection in models designed to simulate vertical and sexual transmission of HIV-1.”
The research, conducted in rhesus macaques and published in Nature, explores how AAV vectors can deliver HIV-neutralizing antibodies to newborns. Broadly neutralizing antibodies (bNAbs) target multiple strains of HIV and have shown efficacy in both clinical and preclinical settings. However, current methods of delivering these antibodies, via repeated injections, are impractical in low-resource settings. The study uses AAV vectors to deliver the genes encoding bNAbs directly into the muscle, turning muscle cells into long-term producers of these protective antibodies.
The researchers focused on a bNAb called 3BNC117, which is known for its potency. They administered the AAV vector to newborn macaques via a single intramuscular injection and tracked the animals over several years.
Age at the time of the gene therapy was found to significantly affect success. Newborn macaques treated within the first four weeks of life showed strong, sustained production of bNAbs and rarely developed anti-drug antibodies (ADAs). In contrast, older infants and juveniles were more likely to produce ADAs, which curtailed bNAb expression. For example, macaques treated at eight or 12 weeks of age often showed short-lived antibody levels because of immune rejection. However, when newborns received the same treatment, all of them maintained durable expression without significant ADA interference.
According to the study, the difference can be attributed to the neonatal immune system's natural tendency toward tolerance rather than immune activation – a mechanism that evolved to prevent the rejection of maternal antigens in utero. When exploring if a child misses that early-life treatment window, the researchers considered whether exposing fetuses to the bNAb in utero could induce tolerance that carries over postnatally. They administered recombinant 3BNC117 to pregnant macaques, then treated their newborns with AAV-bNAb therapy at eight or 12 weeks. All prenatally exposed infants developed sustained bNAb expression with virtually no ADA response, outperforming age-matched peers who had not been exposed in utero. This finding suggests that a classical immune tolerance strategy dating back to Medawar’s transplant experiments could be revived for modern gene therapies.
Long-term follow-up of treated macaques revealed that a single AAV injection at birth provided protection from SHIV (the simian counterpart of HIV) for at least three to four years – longer than the typical breastfeeding duration in regions with high HIV prevalence. When re-exposed to the virus in adolescence through rectal challenges mimicking sexual transmission, the treated macaques showed robust resistance, with only one of six becoming infected – and that case showed milder disease – showing that a “one-shot” intervention in early life can protect against both vertical (mother-to-child) and horizontal (sexual) HIV transmission.
Translating these results to human applications comes with numerous challenges. Differences in body size, immune development, and AAV seroprevalence between species mean dosing and timing would need adjustment. Moreover, AAV therapies are currently expensive and inaccessible in the many low-income countries where the need is most urgent.
AAV vectors, however, are thermally stable, eliminating the need for cold storage, and intramuscular injections are simple to administer in basic healthcare settings. The success of AAV-bNAb therapy for HIV could extend to other infectious diseases too. Malaria, for example, remains a leading cause of death in children under five in developing countries. If monoclonal antibodies against malaria could be similarly delivered via AAV vectors at birth, it could lead to long-lasting protection from a wide range of pediatric infectious threats.
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