HVTN703/HPTN081 + HVTN704/HPTN085 AMP Trials Genotypic Sieve Analysis

In the Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081), prevention efficacy (PE) of the monoclonal broadly neutralizing antibody (bnAb) VRC01 (vs. placebo) against HIV-1 acquisition diagnosis varied according to the HIV-1 Envelope (Env) neutralization sensitivity to VRC01, as measured by 80% inhibitory concentration (IC80). Here, we performed a genotypic sieve analysis, a complementary approach to gaining insight into correlates of protection that assesses how PE varies with HIV-1 sequence features. We analyzed HIV-1 Env amino acid (AA) sequences from the earliest available HIV-1 RNA-positive plasma samples from AMP participants diagnosed with HIV-1 and identified Env sequence features that associated with PE. The strongest Env AA sequence correlate in both trials was VRC01 epitope distance that quantifies the divergence of the VRC01 epitope in an acquired HIV-1 isolate from the VRC01 epitope of reference HIV-1 strains that were most sensitive to VRC01-mediated neutralization. In HVTN 704/HPTN 085, the Env sequence-based predicted probability that VRC01 IC80 against the acquired isolate exceeded 1 µg/mL also significantly associated with PE. In HVTN 703/HPTN 081, a physicochemical-weighted Hamming distance across 50 VRC01 binding-associated Env AA positions of the acquired isolate from the most VRC01-sensitive HIV-1 strain significantly associated with PE. These results suggest that incorporating mutation scoring by BLOSUM62 and weighting by the strength of interactions at AA positions in the epitope:VRC01 interface can optimize performance of an Env sequence-based biomarker of VRC01 prevention efficacy. Future work could determine whether these results extend to other bnAbs and bnAb combinations.在抗体介导预防（Antibody Mediated Prevention, AMP）试验（HVTN 704/HPTN 085与HVTN 703/HPTN 081）中，单克隆广谱中和抗体（broadly neutralizing antibody, bnAb）VRC01相较于安慰剂，针对HIV-1感染诊断的预防效能（prevention efficacy, PE）会随HIV-1包膜（Envelope, Env）对VRC01的中和敏感性变化而变化，其中中和敏感性以80%抑制浓度（80% inhibitory concentration, IC80）进行衡量。本研究开展了基因型筛析分析——这是一种用于解析保护相关性的补充研究方法，可评估预防效能随HIV-1序列特征的变化规律。我们对AMP试验中确诊HIV-1感染的受试者的最早可获取的HIV-1 RNA阳性血浆样本，开展了HIV-1 Env氨基酸（amino acid, AA）序列分析，并鉴定出与预防效能相关的Env序列特征。两项试验中与预防效能相关性最强的Env AA序列指标为VRC01表位距离，该指标可量化所分离到的感染性HIV-1毒株的VRC01表位，与对VRC01介导的中和作用最敏感的参考HIV-1毒株的VRC01表位之间的序列差异。在HVTN 704/HPTN 085试验中，基于Env序列预测的、针对所分离毒株的VRC01 IC80超过1 μg/mL的概率，同样与预防效能存在显著相关性。在HVTN 703/HPTN 081试验中，所分离毒株与对VRC01最敏感的HIV-1毒株之间，在50个与VRC01结合相关的Env AA位点上的理化加权汉明距离，同样与预防效能显著相关。上述结果表明，结合BLOSUM62的突变评分，以及对表位-VRC01界面处氨基酸位点的相互作用强度进行加权，可优化基于Env序列的VRC01预防效能生物标志物的性能。未来研究可进一步探究这些结果是否可推广至其他广谱中和抗体及其联合使用场景。