Centre for HIV and STIs, National Institute for Communicable Diseases (NICD), of the National Health Laboratory Service (NHLS), Johannesburg, 2131, South Africa.
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2000, South Africa.
Nat Commun. 2018 Oct 26;9(1):4489. doi: 10.1038/s41467-018-06794-x.
The α4β7 integrin is a non-essential HIV-1 adhesion receptor, bound by the gp120 V1V2 domain, facilitating rapid viral dissemination into gut-associated lymphoid tissues. Antibodies blocking this interaction early in infection can improve disease outcome, and V1V2-targeted antibodies were correlated with moderate efficacy reported from the RV144 HIV-1 vaccine trial. Monoclonal α4β7-blocking antibodies recognise two slightly different helical V2 conformations, and current structural data suggests their binding sites are occluded in prefusion envelope trimers. Here, we report cocrystal structures of two α4β7-blocking antibodies from an infected donor complexed with scaffolded V1V2 or V2 peptides. Both antibodies recognised the same helix-coil V2 conformation as RV144 antibody CH58, identifying a frequently sampled alternative conformation of full-length V1V2. In the context of Envelope, this α-helical form of V1V2 displays highly exposed α4β7-binding sites, potentially providing a functional role for non-native Envelope on virion or infected cell surfaces in HIV-1 dissemination, pathogenesis, and vaccine design.
α4β7 整合素是一种非必需的 HIV-1 粘附受体，与 gp120 V1V2 结构域结合，促进病毒迅速扩散到肠道相关淋巴组织。在感染早期阻断这种相互作用的抗体可以改善疾病结局，而针对 V1V2 的抗体与 RV144 HIV-1 疫苗试验报告的中等疗效相关。单克隆 α4β7 阻断抗体识别两个略有不同的螺旋 V2 构象，目前的结构数据表明，它们的结合位点在融合前包膜三聚体中被封闭。在这里，我们报告了来自感染供体的两种 α4β7 阻断抗体与支架化 V1V2 或 V2 肽复合物的共晶体结构。两种抗体都识别了与 RV144 抗体 CH58 相同的螺旋-卷曲 V2 构象，鉴定了全长 V1V2 的一种经常采样的替代构象。在包膜的背景下，V1V2 的这种 α-螺旋形式显示出高度暴露的 α4β7 结合位点，这可能为病毒粒子或感染细胞表面上非天然包膜在 HIV-1 传播、发病机制和疫苗设计中的功能作用提供了依据。
J Virol. 2017-8-10
PLoS Pathog. 2023-12
Sci Immunol. 2017-5-12
Zotero 插件
