Conformational Differences between Functional Human Immunodeficiency Virus Envelope Glycoprotein Trimers and Stabilized Soluble Trimers
Conformational Differences between Functional Human Immunodeficiency Virus Envelope Glycoprotein Trimers and Stabilized Soluble Trimers
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DOI：
10.1128/jvi.01709-18
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发表时间：
2019-02-01
影响因子：
5.4
通讯作者：
Sodroski, Joseph
中科院分区：
文献类型：
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作者：
Castillo-Menendez, Luis R.;Nguyen, Hanh T.;Sodroski, Joseph
与受体CD 4的结合触发了人类免疫缺陷病毒1型（HIV-1）包膜糖蛋白（Env）三聚体（gp 120/gp 41）的进入相关构象变化（3）。通过gp 120-gp 41二硫键和gp 41中的变化（I559 P）稳定的可溶形式的HIV-1 Env三聚体（sgp 140 SOSIP.664）已在结构上进行了表征。在这里，我们使用交联/质谱法来评估功能膜Env和sgp 140 SOSIP的构象。664。在gp 120三聚体关联结构域和C末端以及gp 41七肽重复1（HR 1）区域中检测到差异。尽管膜Env三聚体仅在CD 4结合后暴露gp 41 HR 1卷曲螺旋，但即使在不存在CD 4的情况下，gp 41 HR 2肽也可接近sgp 140 SOSIP.664 HR 1卷曲螺旋。我们的研究结果描绘了gp 120和gp 41亚基之间的功能膜Env和sgp 140 SOSIP.664三聚体的差异，并提供距离的限制，可以帮助验证候选人的结构模型的本地HIV-1 Env trimer.IMPORTANCE HIV-1包膜糖蛋白刺突介导的病毒进入宿主细胞，是疫苗诱导的抗体的主要目标。稳定且易于产生的包膜糖蛋白的可溶性形式已被广泛表征，并被认为是疫苗。在这里，我们提出的证据表明，这些稳定的可溶性包膜糖蛋白在多个方面不同于天然的HIV-1包膜糖蛋白。通过精确定位这些差异，我们的研究结果可以指导包膜糖蛋白制剂的改进，以实现与病毒包膜糖蛋白刺突更大的相似性，从而潜在地提高其作为疫苗的有效性。
Binding to the receptor CD4 triggers entry-related conformational changes in the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer, (gp120/gp41)(3). Soluble versions of HIV-1 Env trimers (sgp140 SOSIP.664) stabilized by a gp120-gp41 disulfide bond and a change (I559P) in gp41 have been structurally characterized. Here, we use cross-linking/mass spectrometry to evaluate the conformations of functional membrane Env and sgp140 SOSIP.664. Differences were detected in the gp120 trimer association domain and C terminus and in the gp41 heptad repeat 1 (HR1) region. Whereas the membrane Env trimer exposes the gp41 HR1 coiled coil only after CD4 binding, the sgp140 SOSIP.664 HR1 coiled coil was accessible to the gp41 HR2 peptide even in the absence of CD4. Our results delineate differences in both gp120 and gp41 subunits between functional membrane Env and the sgp140 SOSIP.664 trimer and provide distance constraints that can assist validation of candidate structural models of the native HIV-1 Env trimer.IMPORTANCE HIV-1 envelope glycoprotein spikes mediate the entry of the virus into host cells and are a major target for vaccine-induced antibodies. Soluble forms of the envelope glycoproteins that are stable and easily produced have been characterized extensively and are being considered as vaccines. Here, we present evidence that these stabilized soluble envelope glycoproteins differ in multiple respects from the natural HIV-1 envelope glycoproteins. By pinpointing these differences, our results can guide the improvement of envelope glycoprotein preparations to achieve greater similarity to the viral envelope glycoprotein spike, potentially increasing their effectiveness as a vaccine.