Effects of the I559P gp41 change on the conformation and function of the human immunodeficiency virus (HIV-1) membrane envelope glycoprotein trimer.
Effects of the I559P gp41 change on the conformation and function of the human immunodeficiency virus (HIV-1) membrane envelope glycoprotein trimer.
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DOI：
10.1371/journal.pone.0122111
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Finzi A
中科院分区：
文献类型：
--
作者：
Alsahafi N;Debbeche O;Sodroski J;Finzi A
成熟的人类免疫缺陷病毒（HIV-1）包膜糖蛋白（Env）三聚体是由前体蛋白水解切割产生的，由三个gp 120外部亚基和三个gp 41跨膜亚基组成。亚稳态Env复合物通过gp 120与受体CD 4和CCR 5/CXCR 4的结合而被诱导经历病毒进入所需的构象变化。gp 41胞外域中的异亮氨酸至脯氨酸的变化（I559 P）已被用于稳定HIV-1 Env三聚体的可溶形式，用于结构表征和用作免疫原。在天然膜锚定的HIV-1BG 505 Env中，I559 P的变化适度降低了蛋白水解成熟，增加了gp 120与Env三聚体的非共价结合，并导致Env构象与野生型HIV-1BG 505 Env明显不同。与野生型Env相比，I559 P Env被来自HIV-1感染个体的多克隆血清、几种gp 41定向抗体、一些针对gp 120的CD 4结合位点的抗体以及优先识别CD 4结合Env的抗体无效地识别。野生型HIV-1BG 505 Env和I559 P突变体之间的一些gp 120相关抗原差异被gp 120和gp 41之间的SOS二硫键补偿，该二硫键已用于稳定裂解的可溶性Env三聚体。尽管如此，无论是否存在SOS变化，结合gp 120的CD 4结合位点的VRC 01中和抗体和结合杂合gp 120-gp 41表位的PGT 151中和抗体识别具有脯氨酸559的Envs的效率低于具有异亮氨酸559的Envs。I559 P的变化完全消除了HIV-1BG 505 Env介导细胞-细胞融合和病毒进入的能力，并消除了SOS Env在还原剂存在下支持病毒感染的能力。这些结果表明功能性Env尖峰和I559 P Env的四级结构之间存在差异。
The mature human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer is produced by proteolytic cleavage of a precursor and consists of three gp120 exterior and three gp41 transmembrane subunits. The metastable Env complex is induced to undergo conformational changes required for virus entry by the binding of gp120 to the receptors, CD4 and CCR5/CXCR4. An isoleucine-to-proline change (I559P) in the gp41 ectodomain has been used to stabilize soluble forms of HIV-1 Env trimers for structural characterization and for use as immunogens. In the native membrane-anchored HIV-1BG505 Env, the I559P change modestly decreased proteolytic maturation, increased the non-covalent association of gp120 with the Env trimer, and resulted in an Env conformation distinctly different from that of the wild-type HIV-1BG505 Env. Compared with the wild-type Env, the I559P Env was recognized inefficiently by polyclonal sera from HIV-1-infected individuals, by several gp41-directed antibodies, by some antibodies against the CD4-binding site of gp120, and by antibodies that preferentially recognize the CD4-bound Env. Some of the gp120-associated antigenic differences between the wild-type HIV-1BG505 Env and the I559P mutant were compensated by the SOS disulfide bond between gp120 and gp41, which has been used to stabilize cleaved soluble Env trimers. Nonetheless, regardless of the presence of the SOS changes, Envs with proline 559 were recognized less efficiently than Envs with isoleucine 559 by the VRC01 neutralizing antibody, which binds the CD4-binding site of gp120, and the PGT151 neutralizing antibody, which binds a hybrid gp120-gp41 epitope. The I559P change completely eliminated the ability of the HIV-1BG505 Env to mediate cell-cell fusion and virus entry, and abolished the capacity of the SOS Env to support virus infection in the presence of a reducing agent. These results suggest that differences exist between the quaternary structures of functional Env spikes and I559P Envs.
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