Human immunodeficiency virus type 1 (HIV-1)-specific broadly neutralizing monoclonal antibodies (bNAbs) have to date shown transient viral suppression when administered as monotherapy or as a cocktail of two antibodies^1,2,3,4. A combination of three bNAbs provides improved neutralization coverage of global viruses, which may more potently suppress viral escape and rebound^5,6,7. Here we performed an open-label, two-part study evaluating a single intravenous dose of HIV-1 bNAbs, PGT121, PGDM1400 and VRC07-523LS, in six adults without HIV in part 1 and a multicenter trial of up to six monthly infusions of these three bNAbs in 12 people living with HIV with an antiretroviral therapy (ART) interruption in part 2. The primary endpoints were safety, tolerability and pharmacokinetics, and the secondary endpoints in part 2 were antiviral activity following ART discontinuation, changes in CD4⁺ T cell counts and development of HIV-1 sequence mutations associated with bNAb resistance. The trial met its prespecified endpoints. The bNAb treatment was generally safe and well tolerated. In part 2, 83% of participants (10 of 12) maintained virologic suppression for the duration of antibody therapy for at least 28 weeks, and 42% of participants (5 of 12) showed virologic suppression for at least 38–44 weeks, despite the decline of serum bNAb concentrations to low or undetectable levels. In exploratory analyses, early viral rebound in two individuals correlated with baseline resistance to PGT121 and PGDM1400, whereas long-term virologic control in five individuals correlated with reduced immune activation, T cell exhaustion and proinflammatory signaling following bNAb therapy. Our data show the potential of a triple bNAb cocktail to suppress HIV-1 in the absence of ART. ClinicalTrials.gov registration: NCT03721510.

迄今为止，人类免疫缺陷病毒 1 型 （HIV-1） 特异性广泛中和单克隆抗体 （bNAb） 在作为单一疗法或两种抗体的混合物给药时显示出瞬时病毒抑制^1,2,3,4。三种 bNAb 的组合提供了更好的全球病毒的中和覆盖率，这可能更有效地抑制病毒逃逸和反弹^5,6,7。在这里，我们进行了一项开放标签、分为两部分的研究，在第 1 部分中评估了 6 名没有 HIV 的成年人单次静脉注射 HIV-1 bNAbs、PGT121、PGDM1400 和 VRC07-523LS，以及一项多中心试验，在 12 名 HIV 感染者中每月输注这三种 bNAb，第 2 部分中断抗逆转录病毒治疗 （ART）。主要终点是安全性、耐受性和药代动力学，第 2 部分的次要终点是 ART 停药后的抗病毒活性、CD4⁺ T 细胞计数的变化以及与 bNAb 耐药相关的 HIV-1 序列突变的发展。该试验达到了其预先设定的终点。bNAb 治疗总体上安全且耐受性良好。在第 2 部分中，83% 的参与者（12 人中的 10 人）在抗体治疗期间维持病毒学抑制至少 28 周，42% 的参与者（12 人中的 5 人）显示病毒学抑制至少 38-44 周，尽管血清 bNAb 浓度下降到低或检测不到的水平。在探索性分析中，两个个体的早期病毒反弹与对 PGT121 和 PGDM1400 的基线耐药性相关，而五个个体的长期病毒学控制与 bNAb 治疗后免疫激活减少、T 细胞耗竭和促炎信号相关。 我们的数据显示，在没有 ART 的情况下，三重 bNAb 鸡尾酒具有抑制 HIV-1 的潜力。ClinicalTrials.gov 注册：NCT03721510。