A groundbreaking study published in Nature this year unveils a promising approach to overcoming one of the most formidable obstacles in HIV-1 prevention and treatment: achieving durable expression of broadly neutralizing antibodies (bNAbs) in infants at risk of HIV-1 infection. The research spotlights how prenatal exposure to recombinant bNAbs can induce immune tolerance, drastically limiting the detrimental anti-drug antibody (ADA) responses that typically undermine postnatal gene therapy’s efficacy. This innovative work could redefine strategies aimed at protecting vulnerable neonates worldwide from vertical HIV-1 transmission.
The crux of this issue lies in the inverse correlation between the age at administration of adeno-associated virus (AAV)-vectored bNAb delivery and the level and persistence of protective antibody expression. In simpler terms, the older the infant at the time of treatment, the stronger the immune response against the introduced antibodies, resulting in accelerated clearance and loss of efficacy. Given that many infants who acquire HIV-1 do so postpartum, often through breastfeeding, it remains imperative to explore solutions that enable effective bNAb gene therapy beyond the neonatal window.
The research, led by Ardeshir, O’Hagan, Mehta, and their colleagues, draws inspiration from pioneering immunological studies dating back to the mid-twentieth century. Medawar’s seminal experiments demonstrated that prenatal exposure to allogeneic cells in rodents and birds facilitated immune tolerance to those same cells in adulthood, fundamentally altering transplant acceptance paradigms. Leveraging this principle, the team hypothesized that rhesus macaques exposed in utero to recombinant bNAbs encoded by AAV vectors would develop immune tolerance, thus reducing the likelihood of ADA emergence and enhancing bNAb expression upon postnatal gene therapy.
To rigorously test this hypothesis, the researchers conducted an intricate fourth study involving eight pregnant AAV-8-seronegative rhesus macaque females. These dams were intravenously infused during late gestation with high doses of recombinant rh-3BNC117-IgG1 antibodies. Two groups received variants of the antibody: one with pharmacokinetic-enhancing “LS” mutations (group B) and another lacking these mutations (group C), each dosed at 30 mg/kg. Crucially, maternal-to-fetal IgG transfer, mediated by the neonatal Fc receptor, ensured the recombinant antibody crossed the placenta, exposing fetuses to the therapeutic molecule well before birth.
Remarkably, at the time of cesarean delivery performed approximately two weeks after maternal injection, both rh-3BNC117-IgG1-LS and the non-LS form were detectable in neonatal circulation, confirming effective transplacental antibody transfer. The newborn monkeys were subsequently assigned to two experimental arms: receiving AAV-8-rh-3BNC117-IgG1-LS vectors at either 8 or 12 weeks of age (groups 10 and 11). This design allowed a nuanced analysis of the durability and immunogenicity of the vector-delivered bNAbs postnatally, in infants with versus without prior fetal exposure to the antibody.
Over the subsequent 20 weeks of follow-up, an extraordinary pattern emerged. All eight infants from the prenatally exposed groups mounted persistent and robust expression of the rh-3BNC117-IgG1-LS antibody, with minimal to undetectable ADA responses, a stark contrast to the control cohorts that had no prenatal exposure. Among these unexposed infants, only two out of five demonstrated sustained antibody production. Statistical analyses underscored the significance of this disparity, cementing the prenatal exposure strategy as a powerful modulator of immune tolerance.
Beyond mere presence, the cumulative serum concentrations of the bNAb were substantially higher in the prenatally exposed groups, while their ADA levels were markedly suppressed. These findings strongly imply that in utero exposure to the recombinant antibody induces a state of immune unresponsiveness or tolerance towards the molecule, thereby permitting unimpeded expression from the AAV vector administered weeks later. Such immunological priming effectively “educates” the developing immune system to accept the bNAb as “self,” which bodes well for overcoming ADA-related hurdles that have historically plagued postnatal gene therapies.
The implications of this discovery are far-reaching. Vertically acquired HIV-1 remains a global health challenge, particularly in settings where access to early antiretroviral therapy is limited. By uncovering a strategy that extends the window of effective intervention beyond the immediate neonatal period, this work opens opportunities to protect infants who might otherwise have missed critical early therapy. Moreover, the approach leverages established mechanisms of maternal-fetal IgG transfer, suggesting a translational path compatible with existing clinical practices.
Technically, the study employed careful vector design, choosing AAV serotype 8 due to its tropism and established safety profile, coupled with an IgG1 bNAb scaffold engineered for stability and potency. Notably, the LS mutation incorporated into rh-3BNC117-IgG1-LS extends antibody half-life by enhancing neonatal Fc receptor binding, a modification validated here to augment expression durability. By comparing LS and non-LS variants in prenatal exposure, the researchers strengthened their mechanistic understanding of how pharmacokinetic enhancements may contribute to therapeutic success.
The comprehensive pharmacokinetic profiling conducted in this work further reinforced its conclusions. The maternally administered bNAbs exhibited typical distribution and clearance patterns, indicating that neither the prenatal antibody administration nor subsequent vector-transduced expression elicited overt toxicity or adverse immune activation in the mothers or infants. This safety profile is essential for moving such therapies towards human clinical trials.
While promising, the study also invites further inquiry. It remains to be elucidated how long-lasting this prenatal tolerance mechanism might be and whether it withstands subsequent immunological challenges throughout infancy and beyond. Additionally, exploring the precise cellular and molecular pathways underpinning ADA suppression following prenatal exposure could provide insights relevant to other gene therapies and immune-mediated conditions.
In sum, the meticulous work by Ardeshir, O’Hagan, Mehta, and colleagues demonstrates a compelling paradigm shift in the quest to harness AAV-mediated bNAb delivery against HIV-1. By inducing fetal immune tolerance to therapeutic antibodies, this approach mitigates one of the principal barriers to sustained antibody expression in infants, extending the potential for effective prevention and treatment in early life. This strategy, rooted deeply in immunological principles first illuminated decades ago, now stands poised to revolutionize interventions for pediatric HIV-1, offering a beacon of hope for vulnerable millions worldwide.
Subject of Research:
AAV-mediated delivery of broadly neutralizing antibodies (bNAbs) for HIV-1 prevention in infants and the role of fetal immune tolerance in reducing anti-drug antibody responses.
Article Title:
Determinants of successful AAV-vectored delivery of HIV-1 bNAbs in early life.
Article References:
Ardeshir, A., O’Hagan, D., Mehta, I. et al. Determinants of successful AAV-vectored delivery of HIV-1 bNAbs in early life. Nature (2025). https://doi.org/10.1038/s41586-025-09330-2
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