Comprehensive AIDS Research Center, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
Aaron Diamond AIDS Research Center, 455 First Ave., 7th Floor, New York, NY 10016, USA.
Cell Rep. 2019 May 28;27(9):2593-2607.e5. doi: 10.1016/j.celrep.2019.04.108.
The HIV-1 envelope glycoprotein (Env) maintains a delicate balance between mediating viral entry and escaping antibody neutralization. Adaptation during transmission of neutralization-sensitive Envs with an "open" conformation remains poorly understood. By passaging a replication-competent simian-human immunodeficiency virus carrying a highly neutralization-sensitive Env (SHIV) in rhesus macaques, we show that SHIV develops enhanced replication kinetics associated with neutralization resistance against antibodies and autologous serum. A gp41 substitution, E658K, functions as the major determinant for these properties. Structural modeling and functional verification indicate that the substitution disrupts an intermolecular salt bridge with the neighboring protomer, thereby promoting fusion and facilitating immune evasion. This effect is applicable across diverse HIV-1 subtypes. Our results highlight the critical role of gp41 in shaping the neutralization profile and the overall conformation of Env during viral adaptation. The unique intermolecular salt bridge could potentially be utilized for rational vaccine design involving more stable HIV-1 envelope trimers.
人类免疫缺陷病毒 1 型（HIV-1）包膜糖蛋白（Env）在介导病毒进入和逃避抗体中和作用之间保持着微妙的平衡。在传播过程中，具有“开放”构象的中和敏感 Env 的适应性仍然知之甚少。通过在恒河猴中传代复制有效的携带高度中和敏感包膜（SHIV）的猴免疫缺陷病毒，我们表明 SHIV 发展出增强的复制动力学，同时对中和抗体和自身血清具有耐药性。gp41 取代 E658K 是这些特性的主要决定因素。结构建模和功能验证表明，该取代破坏了与相邻原聚体的分子间盐桥，从而促进融合并有助于免疫逃避。这种效应适用于多种 HIV-1 亚型。我们的结果强调了 gp41 在塑造中和谱和包膜整体构象方面的关键作用，病毒在适应过程中。独特的分子间盐桥可能被用于涉及更稳定的 HIV-1 包膜三聚体的合理疫苗设计。
