Mechanisms of escape from the PGT128 family of anti-HIV broadly neutralizing antibodies.
Mechanisms of escape from the PGT128 family of anti-HIV broadly neutralizing antibodies.
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DOI：
10.1186/s12977-016-0241-5
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发表时间：
2016-02-02
期刊：
影响因子：
3.3
通讯作者：
Doores KJ
中科院分区：
文献类型：
--
作者：
Krumm SA;Mohammed H;Le KM;Crispin M;Wrin T;Poignard P;Burton DR;Doores KJ
针对HIV包膜糖蛋白gp 120上的甘露糖斑块的广泛中和抗体（bnAb）具有使它们成为疫苗设计的理想靶点的若干特征。PGT 125 -131 bnAb家族由于其上级广度和效力而特别令人感兴趣。由该家族识别的重叠表位是复杂的，中和除了骨架介导的与V3环的323 IGDIR 327基序的接触之外，还需要与至少两个N-连接聚糖（N332/N334、N295或N301）的相互作用。我们最近已经表明，该bnAb家族由两种不同的抗体类别组成，其可以在不存在N332的情况下结合甘露糖斑块中聚糖的交替排列，从而限制病毒逃逸。这使我们进一步研究了对PGT 125 -131 bnAb家族的病毒抗性和逃逸机制。使用从PGT 125 -131供体分离的逃逸病毒作为指导，我们表明，突变V3核心蛋白表位和重新定位关键的N-连接糖基化位点是恢复中和敏感性所必需的。有趣的是，对于PGT 125 -131家族内的两种不同的bnAb类别，中和敏感性可以通过不同的途径恢复，这可能在产生识别分歧中很重要。我们证明，观察到的V3突变赋予其他病毒株通过获得功能和逃逸研究中的中和抗性。此外，我们表明，V3环是重要的，在促进混杂结合聚糖内的甘露糖补丁。这些数据突出了V3环在设计免疫原中的重要性，所述免疫原旨在诱导广泛且有效的bnAb，所述bnAb可以混杂地结合甘露糖片。本文的在线版本（doi：10.1186/s12977-016-0241-5）包含补充材料，可供授权用户使用。
Broadly neutralizing antibodies (bnAbs) directed against the mannose-patch on the HIV envelope glycoprotein gp120 have several features that make them desirable targets for vaccine design. The PGT125-131 bnAb family is of particular interest due to its superior breadth and potency. The overlapping epitopes recognized by this family are intricate and neutralization requires interaction with at least two N-linked glycans (N332/N334, N295 or N301) in addition to backbone-mediated contact with the 323IGDIR327 motif of the V3 loop. We have recently shown that this bnAb family consists of two distinct antibody classes that can bind alternate arrangements of glycans in the mannose-patch in the absence of N332 thereby limiting viral escape. This led us to further investigate viral resistance and escape mechanisms to the PGT125-131 bnAb family. Using an escape virus isolated from the PGT125-131 donor as a guide, we show that mutating both the V3 core protein epitope and repositioning critical N-linked glycosylation sites are required to restore neutralization sensitivity. Interestingly, neutralization sensitivity could be restored via different routes for the two distinct bnAb classes within the PGT125-131 family, which may have been important in generating the divergence in recognition. We demonstrate that the observed V3 mutations confer neutralization resistance in other virus strains through both gain-of-function and escape studies. Furthermore, we show that the V3 loop is important in facilitating promiscuous binding to glycans within the mannose-patch. These data highlight the importance of the V3 loop in the design of immunogens aimed at inducing broad and potent bnAbs that can bind promiscuously to the mannose-patch. The online version of this article (doi:10.1186/s12977-016-0241-5) contains supplementary material, which is available to authorized users.