HIV-1 包膜可变区 1 中的罕见双半胱氨酸残基与中和逃逸和广度发展有关

Maria C Hesselman, Marius Zeeb, Peter Rusert, Chloé Pasin, Jennifer Mamrosh, Samuel Kariuki, Michèle Sickmann, Masako M Kaufmann, Daniel Schmidt, Nikolas Friedrich, Karin J Metzner, Audrey Rindler, Herbert Kuster, Craig Adams, Ruwayhida Thebus, Michael Huber, Sabine Yerly, Karoline Leuzinger, Matthieu Perreau, Roger Koller, Günter Dollenmaier, Simona Frigerio, Dylan H Westfall, Wenjie Deng, Allan C DeCamp, Michal Juraska, Srilatha Edupuganti, Nyaradzo Mgodi, Hugh Murrell, Nigel Garrett, Kshitij Wagh, James I Mullins, Carolyn Williamson, Penny L Moore, Huldrych F Günthard, Roger D Kouyos, Alexandra Trkola
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摘要

确定与自然感染中产生中和交叉反应相关的 HIV-1 包膜糖蛋白(Env)特征对于疫苗设计至关重要。在这里,我们描述了V1中存在的额外半胱氨酸(Cys)残基,这些残基在中和广度优秀的人群中富集。利用 CATNAP 数据库中的 65,000 个 V1 序列、AMP 试验和三个大型纵向 HIV 感染队列(SHCS、ZPHI 和 CAPRISA 研究),我们发现在整个感染过程中,带有额外 V1 Cys 的 Env 变体含量较低,并且随着时间的推移,在参与者中的频率会发生波动。我们证明了额外 V1 Cys 与精英血浆中和的独立关联,以及两个额外 Cys 与一个额外 Cys 的强烈偏好,这表明某些 Env 为稳定而引入了额外的二硫键。我们在 34 位 bNAb 供体的 Envs 中观察到了高水平的中和抗性,其中 17.6% 的 Envs 具有带有额外 Cys 的拉长 V1 区域。我们发现,额外的 V1 Cys 会适度增加来自 V2-Apex bNAb 诱导者的 Env 的抗中和能力。通过额外的 V1 Cys 对该 Env 上 bNAb 表位的可及性进行调节,增强了几个区域的表位屏蔽,但增加了 V2 暴露。这表明,由于摆脱了自体中和活性,插入了额外的 V1 Cys,从而产生了一种经过修饰的抗原,这种抗原可能有利于在该供体中诱导 V2 bNAb。总之,我们在 V1 中发现了一个罕见的孪生 Cys 基序,它能增强抗中和能力和 Env 稳定性,与 bNAb 诱导有关,并有可能被纳入未来的 HIV bNAb 免疫原中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development
The identification of HIV-1 Envelope glycoprotein (Env) traits associated with development of neutralization cross-reactivity in natural infection is critical for vaccine design. Here we describe the presence of additional Cysteine (Cys) residues in V1 that are enriched among people with elite neutralization breadth. Using >65,000 V1 sequences from the CATNAP database, the AMP trials and three large longitudinal HIV infection cohorts, the SHCS, ZPHI and CAPRISA studies, we show that Env variants with extra V1 Cys are present at low levels throughout infection and fluctuate in frequency over time within participants. We demonstrate an independent association of extra V1 Cys with elite plasma neutralization, and a strong preference for two versus one extra Cys, suggesting certain Envs introduce an additional disulfide bond for stabilization. We observed high levels of neutralization resistance among Envs from 34 bNAb donors, of which 17.6% had elongated V1 regions with extra Cys. We show that extra V1 Cys moderately increase neutralization resistance in an Env from a V2-Apex bNAb-inducer. Modulation of the accessibility of bNAb epitopes on this Env by extra V1 Cys enhanced epitope shielding of several regions, but increased V2 exposure. This suggests that escape from autologous neutralizing activity drove insertion of the extra V1 Cys, creating a modified antigen that may have favored V2 bNAb induction in this donor. Overall, we identify a rare motif of twin Cys in V1 that confers increased neutralization resistance and Env stabilization, is associated with bNAb induction, and may hold potential for incorporation into future HIV bNAb immunogens.
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