There is a clear need for low-cost, self-applied, long-lasting approaches to prevent human immunodeficiency virus (HIV) infection in both men and women, even with the advent of pre-exposure prophylaxis (PrEP). Broadly neutralizing antibodies represent an option to improve HIV prophylaxis, but intravenous delivery, cold-chain stability requirements, low cervicovaginal concentrations, and cost may preclude their use. Here, we present an approach to express the anti-GP120 broadly neutralizing antibody PGT121 in the primary site of inoculation, the female reproductive tract, using synthetic mRNA. Expression is achieved through aerosol delivery of unformulated mRNA in water. We demonstrated high levels of antibody expression for over 28 days with a single mRNA administration in the reproductive tract of sheep. In rhesus macaques, neutralizing antibody titers in secretions developed within 4 h and simian-HIV (SHIV) infection of ex vivo explants was prevented. Persistence of PGT121 in vaginal secretions and epithelium was achieved through the incorporation of a glycosylphosphatidylinositol (GPI) anchor into the heavy chain of the antibody. Overall, we present a new paradigm to deliver neutralizing antibodies to the female reproductive tract for the prevention of HIV infections.

译文

显然需要低成本,自我应用,持久的方法来预防男性和女性的人类免疫缺陷病病毒 (HIV) 感染,即使出现了接触前预防 (PrEP)。广泛中和抗体是改善HIV预防的一种选择,但是静脉内给药,冷链稳定性要求,低宫颈阴道浓度和成本可能会阻止其使用。在这里,我们提出了一种使用合成mRNA在接种的主要部位女性生殖道中表达anti-GP120的广泛中和抗体PGT121的方法。通过在水中气溶胶递送未配制的mRNA来实现表达。我们在绵羊的生殖道中单次施用mRNA证明了超过28天的高水平抗体表达。在恒河猴中,分泌物中的中和抗体滴度在4小时内产生,并防止了离体外植体的猿猴HIV (SHIV) 感染。PGT121在阴道分泌物和上皮中的持久性是通过将糖基磷脂酰肌醇 (GPI) 锚入抗体的重链中实现的。总体而言,我们提出了一种向女性生殖道提供中和抗体以预防HIV感染的新范式。

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