Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Duke Human Vaccine Institute, Duke University, Durham, NC, USA.
Nat Commun. 2024 Aug 26;15(1):7334. doi: 10.1038/s41467-024-51656-4.
HIV-1 envelope glycoproteins (Envs) of most primary HIV-1 strains exist in closed conformation and infrequently sample open states, limiting access to internal epitopes. Thus, immunogen design aims to mimic the closed Env conformation as preferred target for eliciting broadly neutralizing antibodies (bnAbs). Here we identify incompletely closed Env conformations of 6 out of 13 transmitted/founder (T/F) strains that are sensitive to antibodies that recognize internal epitopes typically exposed on open Envs. A 3.6 Å cryo-electron microscopy structure of unliganded, incompletely closed T/F Envs (1059-SOSIP) reveals protomer motion that increased sampling of states with incompletely closed trimer apex. We reconstruct de novo the post-transmission evolutionary pathway of a second T/F. Evolved viruses exhibit increased Env resistance to cold, soluble CD4 and 19b, all of which correlate with closing of the adapted Env trimer. Lastly, we show that the ultra-broad N6 bnAb efficiently recognizes different Env conformations and exhibits improved antiviral breadth against VRC01-resistant Envs isolated during the first-in-humans antibody-mediated-prevention trial.
HIV-1 包膜糖蛋白（Env）在大多数原始 HIV-1 株中以封闭构象存在，很少能采样到开放状态，这限制了对内部表位的接触。因此，免疫原设计旨在模拟封闭的 Env 构象，作为诱导广泛中和抗体（bnAb）的首选目标。在这里，我们鉴定了 13 株传播/原始（T/F）株中的 6 株存在不完全封闭的 Env 构象，这些构象对识别通常在开放 Env 上暴露的内部表位的抗体敏感。未经配体结合的、不完全封闭的 T/F Env（1059-SOSIP）的 3.6Å 冷冻电镜结构揭示了单体运动，增加了具有不完全封闭三聚体顶端的状态的采样。我们从头重建了第二个 T/F 的传播后进化途径。进化后的病毒对冷、可溶性 CD4 和 19b 的抵抗力增加，所有这些都与适应的 Env 三聚体的关闭相关。最后，我们表明超广谱 N6 bnAb 能够有效地识别不同的 Env 构象，并对在首次人体抗体介导的预防试验中分离到的对 VRC01 耐药的 Env 表现出改善的抗病毒广谱性。
