Could AAV-vectored delivery of broadly neutralizing antibodies (bNAbs) reduce virologic failure in children diagnosed with perinatal HIV?

Antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition, but its success depends on lifelong adherence, which can be challenging for children living with HIV (CLWH) and their caregivers, particularly in resource-limited settings. Passive immunization with HIV-1 broadly neutralizing antibodies (bNAbs) can maintain virologic suppression in CLWH after ART withdrawal and offers a promising complementary strategy. However, current bNAb delivery relies on repeated administrations of clinical-grade protein biologics, an approach that would be difficult to scale in regions with high rates of vertical HIV-1 transmission. Here, we argue that adeno-associated virus (AAV) vector-mediated gene transfer could overcome this limitation by enabling long-term expression of HIV-1 bNAbs in skeletal muscle. We discuss recent preclinical studies showing that a single neonatal administration of AAV vectors to rhesus macaques was safe and resulted in multi-year bNAb expression. Levels were sufficient to block simian-HIV (SHIV) infection in mucosal challenge models of HIV-1 transmission via breastfeeding and sexual intercourse. Ongoing studies are evaluating the potential of this strategy to durably suppress viremia in SHIV-infected rhesus macaques undergoing ART discontinuation. We believe clinical studies are warranted to evaluate the ability of AAV-expressed HIV-1 bNAbs to achieve durable ART-free virologic control in CLWH.