Maturation-Induced Cloaking of Neutralization Epitopes on HIV-1 Particles
Maturation-Induced Cloaking of Neutralization Epitopes on HIV-1 Particles
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DOI：
10.1371/journal.ppat.1002234
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发表时间：
2011-09-01
期刊：
影响因子：
6.7
通讯作者：
Aiken, Christopher
中科院分区：
文献类型：
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作者：
Joyner, Amanda S.;Willis, Jordan R.;Aiken, Christopher
为了具有传染性，HIV-1 颗粒经历了一个成熟过程，涉及 Gag 和 Gag-Pol 多蛋白的蛋白水解裂解。未成熟的颗粒含有高度稳定的球形 Gag 晶格，与靶细胞的融合受到损害。通过截断 gp41 胞质尾部 (CT) 可缓解融合损伤，这表明未成熟病毒核心与颗粒内 gp41 之间的相互作用通过未知机制抑制 HIV-1 融合。我们假设病毒表面的 Env 构象在颗粒成熟过程中通过与 HIV-1 核心的相互作用进行变构调节。为了测试这一点，我们通过免疫荧光成像量化了一组单克隆抗体与成熟和未成熟 HIV-1 颗粒的结合。令人惊讶的是，未成熟颗粒表现出与几种 gp41 特异性抗体的结合显着增强，其中包括两种识别近膜外部区域 (MPER) 并中和不同 HIV-1 毒株的抗体。成熟和未成熟颗粒上表位暴露的几个差异通过 gp41 CT 的截短而消除，从而将未成熟的 HIV-1 融合缺陷与改变的 Env 构象联系起来。我们的结果表明，融合依赖性 Env 构象变化的扰动会导致未成熟颗粒的融合受损。在颗粒成熟过程中掩蔽中和敏感表位可能有助于 HIV-1 免疫逃避，并对针对 gp41 MPER 的疫苗策略具有实际意义。
To become infectious, HIV-1 particles undergo a maturation process involving proteolytic cleavage of the Gag and Gag-Pol polyproteins. Immature particles contain a highly stable spherical Gag lattice and are impaired for fusion with target cells. The fusion impairment is relieved by truncation of the gp41 cytoplasmic tail (CT), indicating that an interaction between the immature viral core and gp41 within the particle represses HIV-1 fusion by an unknown mechanism. We hypothesized that the conformation of Env on the viral surface is regulated allosterically by interactions with the HIV-1 core during particle maturation. To test this, we quantified the binding of a panel of monoclonal antibodies to mature and immature HIV-1 particles by immunofluorescence imaging. Surprisingly, immature particles exhibited markedly enhanced binding of several gp41-specific antibodies, including two that recognize the membrane proximal external region (MPER) and neutralize diverse HIV-1 strains. Several of the differences in epitope exposure on mature and immature particles were abolished by truncation of the gp41 CT, thus linking the immature HIV-1 fusion defect with altered Env conformation. Our results suggest that perturbation of fusion-dependent Env conformational changes contributes to the impaired fusion of immature particles. Masking of neutralization-sensitive epitopes during particle maturation may contribute to HIV-1 immune evasion and has practical implications for vaccine strategies targeting the gp41 MPER.