早期生命中AAV载体成功递送HIV-1 bNAbs的决定因素，这一成果由佛罗里达大学Mauricio A. Martins研究团队经过不懈努力而取得。相关论文于2025年7月30日发表在《自然》杂志上。

鉴于广泛中和抗体（bNAbs）有望预防HIV-1，研究组假设新生儿分娩的bNAbs主题为腺相关病毒（AAV）可以在婴儿期提供持久的HIV-1免疫。以猕猴（Macaca mulatta）为模型，研究人员发现，在出生时一次性给药编码bNAb 3BNC117的AAV载体，可以在不重新给药的情况下保持bNAb表达超过三年。在模拟HIV-1通过母乳喂养和性交传播的粘膜攻击模型中，这种方法显著地保护了婴儿和青春期前恒河猴免受猿人免疫缺陷病毒的感染。AAV-3BNC117给药时的年龄是成功的主要决定因素，并且与限制bNAb表达的宿主抗药物抗体的发生率呈负相关。与新生儿耐受原则一致，在给药AAV-3BNC117后，新生恒河猴的bNAb表达水平高于年龄较大的婴儿和幼年恒河猴。

此外，在子宫内暴露于重组3BNC117可抑制抗药物抗体，并改善AAV载体在大龄婴儿中的bNAb递送。他们的研究结果表明，新生儿和胎儿的免疫耐受可以用来改善灵长类动物出生后AAV对HIV-1 bNAbs的递送。由于恒河猴出生时一次性接种AAV载体可产生长达数年的HIV-1免疫，因此未来的研究应评估这一策略在预防围产期和青少年人类HIV-1感染方面的能力。

据了解，尽管在HIV-1预防方面取得了进展，但垂直传播在发展中国家仍然是一个紧迫的问题。

附：英文原文

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

Author: Ardeshir, Amir, OHagan, Daniel, Mehta, Isha, Shandilya, Siddhartha, Hopkins, Lincoln L. J., Adamson, Lourdes, Kuroda, Marcelo J., Hahn, Patricia A., da Costa, Lucas A. B., Fuchs, Sebastian P., Martinez-Navio, Jose M., Gardner, Matthew R., Van Rompay, Koen K. A., Magnani, Diogo M., Lifson, Jeffrey D., Gao, Guangping, Farzan, Michael, Desrosiers, Ronald C., Das, Jishnu, Martins, Mauricio A.

Issue&Volume: 2025-07-30

Abstract: Despite advances in HIV-1 prophylaxis, vertical transmission remains a pressing problem in developing countries1. Given the promise of broadly neutralizing antibodies (bNAbs) for HIV-1 prevention2, we hypothesized that neonatal delivery of bNAbs using adeno-associated virus (AAV) could provide durable HIV-1 immunity during infancy. Here, using infant rhesus macaques (Macaca mulatta) as a model, we show that a one-time administration of an AAV vector encoding bNAb 3BNC117 at birth led to sustained bNAb expression for more than three years without redosing. This approach significantly protected both infant and pre-adolescent rhesus macaques from infection with simian–human immunodeficiency virus in mucosal challenge models that mimic HIV-1 transmission through breastfeeding and sexual intercourse. Age at the time of AAV-3BNC117 administration was a main determinant of success and was inversely correlated with the incidence of host anti-drug antibodies that restricted bNAb expression. Consistent with principles of neonatal tolerance3,4, newborn rhesus macaques exhibited higher levels of bNAb expression than older infants and juveniles following AAV-3BNC117 dosing. Furthermore, in utero exposure to recombinant 3BNC117 suppressed anti-drug antibodies and improved AAV-vectored delivery of this bNAb in older infants. Thus, our results suggest that neonatal and fetal immunological tolerance can be leveraged to improve postnatal AAV delivery of HIV-1 bNAbs in primates. Since years-long HIV-1 immunity can be generated in rhesus macaques from a one-time AAV vector administration at birth, future studies should evaluate the ability of this strategy to prevent perinatal and adolescent HIV-1 infections in humans.

DOI: 10.1038/s41586-025-09330-2

Source: https://www.nature.com/articles/s41586-025-09330-2