Wagh Kshitij, Bhattacharya Tanmoy, Williamson Carolyn, Robles Alex, Bayne Madeleine, Garrity Jetta, Rist Michael, Rademeyer Cecilia, Yoon Hyejin, Lapedes Alan, Gao Hongmei, Greene Kelli, Louder Mark K, Kong Rui, Karim Salim Abdool, Burton Dennis R, Barouch Dan H, Nussenzweig Michel C, Mascola John R, Morris Lynn, Montefiori David C, Korber Bette, Seaman Michael S
Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
Santa Fe Institute, Santa Fe, New Mexico, United States of America.
PLoS Pathog. 2016 Mar 30;12(3):e1005520. doi: 10.1371/journal.ppat.1005520. eCollection 2016 Mar.
The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.
新一代强效广谱中和HIV-1抗体（bnAbs）的发现，引发了人们对其在预防和/或治疗HIV-1感染方面潜在用途的浓厚兴趣。虽然可能需要组合靶向病毒包膜（Env）上不同表位的bnAbs，以克服HIV-1的极端多样性，但一个关键的突出问题是，需要哪些bnAbs以及多少数量才能实现最佳临床效益。我们评估了15种靶向Env四个不同表位的bnAbs的中和活性，这些表位包括CD4结合位点（CD4bs）、V1/V2聚糖区域、V3聚糖区域和gp41膜近端外部区域（MPER），针对一组200种急性/早期C亚型HIV-1 Env假病毒。我们开发了一个数学模型，该模型能够高精度预测通过实验评估的bnAb组合子集的中和作用。利用这个模型，我们对超过1600种可能的双抗体、三抗体和四抗体bnAb组合的预测中和活性进行了全面系统的比较。不仅根据中和的广度和效力，还根据其他相关指标，如完全中和程度和瞬时抑制潜力（IIP），确定了最有前景的bnAb组合。根据这组标准，确定了三抗体和四抗体组合，它们比最佳双抗体组合显著更有效，并进一步提高了多种bnAbs同时对给定病毒具有活性的概率，这一要求对于在体内对抗逃逸可能至关重要。这些结果为将具有最佳体外成功预测指标的bnAb组合推进到HIV-1感染预防和治疗的临床试验提供了理论依据。
