Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA.
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY.
AIDS. 2021 Aug 1;35(10):1567-1574. doi: 10.1097/QAD.0000000000002934.
The opioid epidemic has increased parentally acquired HIV infection. To inform the development of a long-acting prevention strategy, we evaluated the protective efficacy of broadly neutralizing antibodies (bNAbs) against intravenous simian-human immunodeficiency virus (SHIV) infection in macaques.
Five cynomolgus macaques were injected once subcutaneously with 10-1074 and 3BNC117 (10 mg each kg-1) and were repeatedly challenged intravenously once weekly with SHIVAD8-EO (130 TCID50), until infection was confirmed via plasma viral load assay. Two control macaques, which received no antibody, were challenged identically.
Plasma viremia was monitored via RT-qPCR assay. bNAb concentrations were determined longitudinally in plasma samples via TZM-bl neutralization assays using virions pseudotyped with 10-1074-sensitive (X2088_c9) or 3BNC117-sensitive (Q769.d22) HIV envelope proteins.
Passively immunized macaques were protected against a median of five weekly intravenous SHIV challenges, as compared to untreated controls, which were infected following a single challenge. Of the two bNAbs, 10-1074 exhibited relatively longer persistence in vivo. The median plasma level of 10-1074 at SHIV breakthrough was 1.1 μg ml-1 (range: 0.6-1.6 μg ml-1), whereas 3BNC117 was undetectable. Probit modeling estimated that 6.6 μg ml-1 of 10-1074 in plasma corresponded to a 99% reduction in per-challenge infection probability, as compared to controls.
Significant protection against repeated intravenous SHIV challenges was observed following administration of 10-1074 and 3BNC117 and was due primarily to 10-1074. Our findings extend preclinical studies of bNAb-mediated protection against mucosal SHIV acquisition and support the possibility that intermittent subcutaneous injections of 10-1074 could serve as long-acting preexposure prophylaxis for persons who inject drugs.
阿片类药物滥用流行导致了母婴传播的艾滋病毒感染增加。为了为长效预防策略的制定提供信息，我们评估了广谱中和抗体（bnAb）对恒河猴静脉内感染猴免疫缺陷病毒（SHIV）的保护效力。
五只食蟹猴接受了一次皮下注射 10-1074 和 3BNC117（各 10mg/kg），每周静脉内重复接受一次 SHIVAD8-EO（130 TCID50）挑战，直到通过血浆病毒载量检测确证感染。两只未接受抗体的对照猴以相同方式接受挑战。
通过 RT-qPCR 检测监测血浆病毒血症。通过使用包膜蛋白 X2088_c9 或 Q769.d22 假型化的病毒颗粒，在 TZM-bl 中和测定中，纵向测定血浆样本中的 bnAb 浓度。
与未治疗的对照组相比，接受被动免疫的猕猴受到保护，可防止中位数为 5 次每周静脉内 SHIV 挑战，而对照组在单次挑战后即被感染。两种 bnAb 中，10-1074 在体内的持久性相对较长。在 SHIV 突破时，10-1074 的中位血浆水平为 1.1μg/ml（范围：0.6-1.6μg/ml），而 3BNC117 无法检测到。概率建模估计，与对照组相比，血浆中 6.6μg/ml 的 10-1074 对应于每次挑战感染概率降低 99%。
在给予 10-1074 和 3BNC117 后，观察到对重复静脉内 SHIV 挑战的显著保护，主要归因于 10-1074。我们的发现扩展了 bnAb 介导的黏膜 SHIV 获得性保护的临床前研究，并支持间歇性皮下注射 10-1074 可作为注射吸毒者的长效暴露前预防的可能性。
