与受体结合,CD4,驱动预先触发的,人类免疫缺陷病毒(HIV-1)包膜糖蛋白(Env)三聚体([gp120/gp41]3)的“封闭”(State-1)构象更多的“开放”构象。病毒膜上的HIV-1Env维持在State-1构象,其抵抗通常引发的抗体的结合和中和。在病毒与靶细胞接合之前过早触发Env通常导致对自发失活或配体诱导的中和的敏感性增加。这里,我们发现原发性HIV-1株gp41膜近端区(MPER)中的单个氨基酸取代导致病毒表型,表明Env过早触发下游构象.具体来说,MPER的变化降低了病毒的感染性,并在全球范围内增加了病毒对不良中和抗体的敏感性,可溶性CD4,一种CD4模拟化合物,和暴露在寒冷中。相比之下,MPER突变体对状态1-优选抑制剂的敏感性降低,BMS-806和PGT151广泛中和抗体。从病毒颗粒中消耗胆固醇不会产生与MPER改变相同的状态1不稳定表型。值得注意的是,远离MPER的Env的状态1稳定变化可以最大程度地减少MPER改变的表型效应,但不影响病毒对胆固醇消耗的敏感性。因此,膜近端gp41元件有助于维持预触发的Env构象。MPER变化的构象破坏性影响可以通过远程状态1稳定环境修饰来最小化,一种策略,可能有助于保留Env的本地预触发状态。重要性人类免疫缺陷病毒(HIV-1)包膜糖蛋白(Env)的预触发形状是可以中和许多病毒株的抗体的主要靶标。有效的HIV-1疫苗可能需要提高这些类型的抗体,但事实证明,这个目标很困难。一个原因是Env的预触发形状是不稳定的并且依赖于病毒膜附近的相互作用。这里,我们表明,Env的膜近端外部区域(MPER)在维持Env处于预触发形状中起着重要作用。MPER的改变导致Env构象的全球变化,从而破坏了其预触发的形状。我们还发现,MPER变化的这些破坏性影响可以通过稳定预触发形状的远距离Env修饰来最小化。这些修饰可用于保留用于结构和疫苗研究的Env的天然形状。
Binding to the receptor, CD4, drives the pretriggered, \"closed\" (State-1) conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer ([gp120/gp41]3) into more \"open\" conformations. HIV-1 Env on the viral membrane is maintained in a State-1 conformation that resists binding and neutralization by commonly elicited antibodies. Premature triggering of Env before the virus engages a target cell typically leads to increased susceptibility to spontaneous inactivation or ligand-induced neutralization. Here, we showed that single amino acid substitutions in the gp41 membrane-proximal external region (
MPER) of a primary HIV-1 strain resulted in viral phenotypes indicative of premature triggering of Env to downstream conformations. Specifically, the
MPER changes reduced viral infectivity and globally increased virus sensitivity to poorly neutralizing antibodies, soluble CD4, a CD4-mimetic compound, and exposure to cold. In contrast, the
MPER mutants exhibited decreased sensitivity to the State 1-preferring inhibitor, BMS-806, and to the PGT151 broadly neutralizing antibody. Depletion of cholesterol from virus particles did not produce the same State 1-destabilizing phenotypes as MPER alterations. Notably, State 1-stabilizing changes in Env distant from the
MPER could minimize the phenotypic effects of
MPER alteration but did not affect virus sensitivity to cholesterol depletion. Thus, membrane-proximal gp41 elements contribute to the maintenance of the pretriggered Env conformation. The conformationally disruptive effects of MPER changes can be minimized by distant State 1-stabilizing Env modifications, a strategy that may be useful in preserving the native pretriggered state of Env. IMPORTANCE The pretriggered shape of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) is a major target for antibodies that can neutralize many strains of the virus. An effective HIV-1 vaccine may need to raise these types of antibodies, but this goal has proven difficult. One reason is that the pretriggered shape of Env is unstable and dependent on interactions near the viral membrane. Here, we showed that the membrane-proximal external region (MPER) of Env plays an important role in maintaining Env in a pretriggered shape. Alterations in the MPER resulted in global changes in Env conformation that disrupted its pretriggered shape. We also found that these disruptive effects of MPER changes could be minimized by distant Env modifications that stabilized the pretriggered shape. These modifications may be useful for preserving the native shape of Env for structural and vaccine studies.