Data from: The W100 pocket on HIV-1 gp120 penetrated by b12 is not a target for other CD4bs monoclonal antibodies

BACKGROUND: The conserved CD4 binding site (CD4bs) on HIV-1 gp120 is a major target for vaccines. It is a priority to determine sites and structures within the CD4bs that are important for inclusion in vaccines. We studied a gp120 pocket penetrated by W100 of the potent CD4bs monoclonal antibody (mab), b12. We compared HIV-1 envelopes and corresponding mutants that carried blocked W100 pockets to evaluate whether other CD4bs mabs target this site. FINDINGS: All CD4bs mabs tested blocked soluble CD4 binding to gp120 consistent with their designation as CD4bs directed antibodies. All CD4bs mabs tested (except for b12) neutralized pseudovirions carrying NL4.3 wt envelope. However, only b12 failed to neutralize pseudoviruses carrying mutant envelopes with a blocked W100 pocket. Similarly, for CD4bs mabs that neutralized pseudovirions carrying primary envelopes, mutation of the W100 pocket had little or no effect on neutralization sensitivity. CONCLUSIONS: Our data indicate that the b12 W100 pocket on gp120 is targeted infrequently by CD4bs mabs. This site is therefore not a priority for preservation in vaccines aiming to elicit antibodies targeting the CD4bs.

研究背景：HIV-1 gp120上的保守CD4结合位点（CD4 binding site，CD4bs）是疫苗研发的核心靶点。明确CD4bs内适合纳入疫苗设计的关键位点与结构，是当前HIV疫苗研发的重点方向。我们针对强效CD4bs单克隆抗体（monoclonal antibody，mab）b12的W100残基所穿透的gp120口袋结构展开研究，对比了携带封闭型W100口袋的HIV-1包膜蛋白及其对应突变体，以探究其他CD4bs单抗是否靶向该位点。研究结果：所有受试CD4bs单抗均能阻断可溶性CD4与gp120的结合，这与其归类为CD4bs靶向抗体的属性完全一致。除b12外，所有受试CD4bs单抗均可中和携带NL4.3野生型包膜的假病毒。但仅b12无法中和携带封闭W100口袋的突变包膜的假病毒。类似地，对于能够中和携带原代分离株包膜的假病毒的CD4bs单抗而言，W100口袋的突变对其中和敏感性几乎无影响。研究结论：本研究数据表明，gp120上的b12 W100口袋极少被CD4bs单抗靶向。因此，对于旨在诱导靶向CD4bs抗体的疫苗而言，该位点并非优先保留的靶点。