In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. Here, we introduced two mutations encoding amino acid substitutions (M428L and N434S, collectively referred to as 'LS') into the genes encoding the crystallizable fragment domains of the highly potent HIV-specific 3BNC117 and 10-1074 bNAbs to increase their half-lives and evaluated their efficacy in blocking infection following repeated low-dose mucosal challenges of rhesus macaques (Macaca mulatta) with the tier 2 SHIV_AD8-EO. A single intravenous infusion of 10-1074-LS monoclonal antibodies markedly delayed virus acquisition for 18 to 37 weeks (median, 27 weeks), whereas the protective effect of the 3BNC117-LS bNAb was more modest (provided protection for 11-23 weeks; median, 17 weeks). Serum concentrations of the 10-1074-LS monoclonal antibody gradually declined and became undetectable in all recipients between weeks 26 and 41, whereas the 3BNC117-LS bNAb exhibited a shorter half-life. To model immunoprophylaxis against genetically diverse and/or neutralization-resistant HIV-1 strains, a combination of the 3BNC117-LS plus 10-1074-LS monoclonal antibodies was injected into macaques via the more clinically relevant subcutaneous route. Even though the administered mixture contained an amount of each bNAb that was nearly threefold less than the quantity of the single monoclonal antibody in the intravenous injections, the monoclonal antibody combination still protected macaques for a median of 20 weeks. The extended period of protection observed in macaques for the 3BNC117-LS plus 10-1074-LS combination could translate into an effective semiannual or annual immunoprophylaxis regimen for preventing HIV-1 infections in humans.

中文翻译：

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单次注射可结晶的片段结构域修饰的抗体可引发对SHIV感染的持久保护。

在没有针对HIV-1的有效且安全的疫苗的情况下，广泛中和抗体（bNAbs）的使用代表了防止病毒传播的合乎逻辑的替代方法。在这里，我们向编码高度有效的HIV特异性3BNC117和10-1074 bNAb的可结晶片段结构域的基因中引入了两个编码氨基酸取代的突变（M428L和N434S，统称为“ LS”），以增加其半衰期并评估了其在使用2级SHIV _{AD8-EO进行的}小剂量恒河猴（Macaca mulatta）反复低剂量粘膜刺激后的阻断感染效果。一次静脉内输注10-1074-LS单克隆抗体会明显延迟病毒获取18到37周（中位数为27周），而3BNC117-LS bNAb的保护作用则较弱（提供11-23周的保护；仅提供11-23周的保护）。中位数，为17周）。10-1074-LS单克隆抗体的血清浓度逐渐下降，在第26周到第41周之间在所有接受者中均无法检测到，而3BNC117-LS bNAb则显示出较短的半衰期。为了模拟针对遗传多样性和/或抗中和性的HIV-1菌株的免疫预防，通过更临床相关的皮下途径将3BNC117-LS和10-1074-LS单克隆抗体的组合注射到猕猴中。即使所施用的混合物中每种bNAb的量几乎比静脉注射中单一单克隆抗体的量少三倍，但单克隆抗体组合仍能保护猕猴长达20周。在猕猴中观察到的3BNC117-LS加10-1074-LS组合的保护期延长，可以转化为预防人类HIV-1感染的有效的半年度或年度免疫预防方案。