Membrane-Proximal External HIV-1 gp41 Motif Adapted for Destabilizing the Highly Rigid Viral Envelope
Membrane-Proximal External HIV-1 gp41 Motif Adapted for Destabilizing the Highly Rigid Viral Envelope
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DOI：
10.1016/j.bpj.2011.10.005
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发表时间：
2011-11-16
影响因子：
3.4
通讯作者：
Nieva, Jose L.
中科院分区：
文献类型：
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作者：
Apellaniz, Beatriz;Ivankin, Andrey;Nieva, Jose L.
电子显微镜结构测定表明，糖蛋白41（gp 41）的膜近端外部区域（MPER）可能与HIV-1的膜界面。进一步提出，在病毒融合过程中，MPR诱导的脂质双层的破坏和/或变形随之发生。然而，据预测，该膜的胆固醇含量（类似于45摩尔%）将对MPER结合和重组活性起作用，这与提出MPER构成不插入病毒膜的gp 41胞外域组分的替代结构模型一致。在这里，使用基于MPR的肽，我们测试的假设，胆固醇阻碍膜协会和不稳定的活动，这个gp 41域。为此，在脂质囊泡中进行的分区和泄漏分析与X射线反射率和掠入射衍射单层的研究相结合。CpreTM是一种结合羧基末端MPER序列和跨膜结构域氨基末端残基的肽，有效地结合和不稳定富含胆固醇的膜。因此，病毒粒子与该肽孵育有效但非特异性地抑制细胞感染。因此，CpreTM似乎模拟MPER结构域的干扰功能，并显示抗病毒活性。因此，我们推断，CpreTM结合胆固醇富集膜将代表抗HIV-1免疫原和抑制剂开发的相关目标。
Electron microscopy structural determinations suggest that the membrane-proximal external region (MPER) of glycoprotein 41 (gp41) may associate with the HIV-1 membrane interface. It is further proposed that MPER-induced disruption and/or deformation of the lipid bilayer ensue during viral fusion. However, it is predicted that the cholesterol content of this membrane (similar to 45 mol %) will act against MPER binding and restructuring activity, in agreement with alternative structural models proposing that the MPER constitutes a gp41 ectodomain component that does not insert into the viral membrane. Here, using MPER-based peptides, we test the hypothesis that cholesterol impedes the membrane association and destabilizing activities of this gp41 domain. To that end, partitioning and leakage assays carried out in lipid vesicles were combined with x-ray reflectivity and grazing-incidence diffraction studies of monolayers. CpreTM, a peptide combining the carboxyterminal MPER sequence with aminoterminal residues of the transmembrane domain, bound and destabilized effectively cholesterol-enriched membranes. Accordingly, virion incubation with this peptide inhibited cell infection potently but nonspecifically. Thus, CpreTM seems to mimic the envelope-perturbing function of the MPER domain and displays antiviral activity. As such, we infer that CpreTM bound to cholesterol-enriched membranes would represent a relevant target for anti-HIV-1 immunogen and inhibitor development.