HIV-1 broadly neutralizing antibody extracts its epitope from a kinked gp41 ectodomain region on the viral membrane
HIV-1 broadly neutralizing antibody extracts its epitope from a kinked gp41 ectodomain region on the viral membrane
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DOI：
10.1016/j.immuni.2007.11.018
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发表时间：
2008-01-01
期刊：
影响因子：
32.4
通讯作者：
Reinherz, Ellis L.
中科院分区：
文献类型：
--
作者：
Sun, Zhen-Yu J.;Oh, Kyoung Joon;Reinherz, Ellis L.
尽管在自然人类感染期间很少引起，但针对不同人类免疫缺陷病毒（HIV）-1株的最广泛中和抗体（BNAb）靶向病毒gp 41的近膜胞外域（MPER）。为了深入了解MPER抗原性、免疫原性和病毒功能，我们通过核磁共振（NMR）、电子顺磁共振（EPR）和表面等离子体共振（SPR）技术的组合研究了其在脂质环境中的结构。分析显示，倾斜的N-末端α螺旋（aa 664-672）通过短铰链连接到平坦的C-末端螺旋段（675-683）。这种亚稳态L形结构浸入病毒膜中，因此不太容易受到免疫攻击。尽管如此，4 E10 BNAb提取物在与表面包埋的MPER初次接触后掩埋了W 672和F673。这些数据表明，BNAb可能如何干扰色氨酸残基相关的病毒融合，涉及移动的N-末端MPER片段，并考虑到HIV-1，HIV-2和SIV中MPER序列的保守性，对结构指导的疫苗设计具有重要意义。
Although rarely elicited during natural human infection, the most broadly neutralizing antibodies (BNAbs) against diverse human immunodeficiency virus (HIV)-1 strains target the membrane-proximal ectodomain region (MPER) of viral gp41. To gain insight into MPER antigenicity, immunogenicity, and viral function, we studied its structure in the lipid environment by a combination of nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and surface plasmon resonance (SPR) techniques. The analyses revealed a tilted N-terminal alpha helix (aa 664-672) connected via a short hinge to a flat C-terminal helical segment (675-683). This metastable L-shaped structure is immersed in viral membrane and, therefore, less accessible to immune attack. Nonetheless, the 4E10 BNAb extracts buried W672 and F673 after initial encounter with the surface-embedded MPER. The data suggest how BNAbs may perturb tryptophan residue-associated viral fusion involving the mobile N-terminal MPER segment and, given conservation of MPER sequences in HIV-1, HIV-2, and SIV, have important implications for structure-guided vaccine design.