Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development

IF 18.7 1区医学 Q1 MICROBIOLOGY Cell host & microbe Pub Date : 2025-02-04 DOI:10.1016/j.chom.2025.01.004

Maria C. Hesselman, Marius Zeeb, Peter Rusert, Chloé Pasin, Jennifer Mamrosh, Samuel Kariuki, Ian Pichler, 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, Alexandra Trkola

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Abstract

Identifying HIV-1 envelope (Env) traits associated with neutralization cross-reactivity is crucial for vaccine design. Variable loops 1 and 2 (V1V2), positioned at the Env trimer apex, are key regions linked to neutralization. We describe non-canonical cysteine (Cys) residues in V1 that are enriched in individuals with elite neutralization breadth. Analyzing over 65,000 V1 sequences from the CATNAP database, AMP trials, and longitudinal HIV-1 cohorts (SHCS, ZPHI, and CAPRISA), we found that Env variants with extra V1 Cys are present at low levels and fluctuate over time. Extra V1 Cys associate with elite plasma neutralization, and two additional Cys are preferred, suggesting stabilization through disulfide bonds. Among 34 broadly neutralizing antibody (bnAb)-inducer Envs, 17.6% had elongated V1 regions with extra Cys. These extra Cys moderately increased neutralization resistance and altered bnAb epitope accessibility. Collectively, altering epitope exposure alongside Env stabilization renders the V1 twin Cys motif a promising feature for HIV-1 bnAb immunogens.

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HIV-1包膜可变区1中罕见的双半胱氨酸残基与中和逃逸和宽度发育有关

鉴定与中和交叉反应性相关的HIV-1包膜（Env）特征对疫苗设计至关重要。位于Env三聚体顶端的可变环1和2 （V1V2）是与中和相关的关键区域。我们描述了V1中的非典型半胱氨酸（Cys）残基，这些残基在具有精英中和宽度的个体中富集。分析了来自CATNAP数据库、AMP试验和HIV-1纵向队列（SHCS、ZPHI和CAPRISA）的65,000多个V1序列，我们发现具有额外V1 Cys的Env变体存在于低水平且随时间波动。额外的V1 Cys与精英等离子体中和有关，另外两个Cys是首选，表明通过二硫键稳定。在34个广泛中和抗体（bnAb）诱导剂Envs中，17.6%的Envs具有延长的V1区和额外的Cys。这些额外的Cys适度增加了中和抗性和改变了bnAb表位的可及性。总的来说，改变表位暴露和Env稳定使得V1双Cys基序成为HIV-1 bnAb免疫原的一个有希望的特征。

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来源期刊

Cell host & microbe 生物-微生物学

CiteScore

45.10

自引率

1.70%

发文量

201

审稿时长

4-8 weeks

期刊介绍： Cell Host & Microbe is a scientific journal that was launched in March 2007. The journal aims to provide a platform for scientists to exchange ideas and concepts related to the study of microbes and their interaction with host organisms at a molecular, cellular, and immune level. It publishes novel findings on a wide range of microorganisms including bacteria, fungi, parasites, and viruses. The journal focuses on the interface between the microbe and its host, whether the host is a vertebrate, invertebrate, or plant, and whether the microbe is pathogenic, non-pathogenic, or commensal. The integrated study of microbes and their interactions with each other, their host, and the cellular environment they inhabit is a unifying theme of the journal. The published work in Cell Host & Microbe is expected to be of exceptional significance within its field and also of interest to researchers in other areas. In addition to primary research articles, the journal features expert analysis, commentary, and reviews on current topics of interest in the field.