Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope.
Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope.
复制标题
菌株特异性和广泛中和反应之间的合作有限的病毒逃逸，并延长了广泛中和表位的暴露。
DOI：
10.1128/jvi.00828-17
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发表时间：
2017-09-15
影响因子：
5.4
通讯作者：
Williamson C
中科院分区：
文献类型：
--
作者：
Anthony C;York T;Bekker V;Matten D;Selhorst P;Ferreria RC;Garrett NJ;Karim SSA;Morris L;Wood NT;Moore PL;Williamson C
V3-聚糖靶向广泛中和抗体（bNAb）是HIV-1疫苗开发的焦点。了解刺激这些抗体发展的病毒动力学可以为免疫原设计提供见解。我们使用深度测序方法以及中和表型分析，研究了与供体CAP 177中V3/C3区域的重叠早期菌株特异性中和抗体（ssNAb）应答相比，V3聚糖导向bNAb逃逸的速率和复杂性。通过N334-至-N332聚糖转换，从ssNAb反应中逃逸迅速发生，仅用7.5周就达到>50%的频率。相反，从bNAb逃逸是通过多种途径介导的，需要更长的时间，逃逸首先通过V1环长度的增加发生，这需要46周才能达到50%的频率，然后是N332到N334的逆转，这需要66周。重要的是，bNAb逃逸是不完全的，同时中和观察到长达3年感染后。ssNAb反应和bNAb反应均受N332聚糖存在/不存在的调节，表明两个表位之间存在重叠。因此，ssNAb维持N332聚糖的选择性压力可能限制了bNAb逃逸途径。这种较慢且不完全的病毒逃逸导致bNAb表位的延长暴露，这反过来可能有助于bNAb谱系的成熟。HIV-1疫苗的开发至关重要，广泛中和抗体可能是保护性疫苗的关键组成部分。靶向V3聚糖的bNAb应答是最有希望的疫苗靶标之一，因为它们通常在感染期间被引发。了解病毒进化和这些抗体的发展之间的相互作用提供了可能指导免疫原设计的见解。我们的工作对比了早期菌株特异性抗体的动力学和后来对常见Env靶标（V3 C3）的广泛中和反应，显示出从bNAb逃逸的速度更慢，更复杂。约束bNAb逃逸，连同同期自体病毒中和的证据，支持bNAb表位的延长暴露使bNAb谱系成熟的建议。
V3-glycan-targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep-sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan-directed bNAbs compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly via an N334-to-N332 glycan switch, which took just 7.5 weeks to reach >50% frequency. In contrast, escape from the bNAbs was mediated via multiple pathways and took longer, with escape first occurring through an increase in V1 loop length, which took 46 weeks to reach 50% frequency, followed by an N332-to-N334 reversion, which took 66 weeks. Importantly, bNAb escape was incomplete, with contemporaneous neutralization observed up to 3 years postinfection. Both the ssNAb response and the bNAb response were modulated by the presence/absence of the N332 glycan, indicating an overlap between the two epitopes. Thus, selective pressure by ssNAbs to maintain the N332 glycan may have constrained the bNAb escape pathway. This slower and incomplete viral escape resulted in prolonged exposure of the bNAb epitope, which may in turn have aided the maturation of the bNAb lineage. IMPORTANCE The development of an HIV-1 vaccine is of paramount importance, and broadly neutralizing antibodies are likely to be a key component of a protective vaccine. The V3-glycan-targeting bNAb responses are among the most promising vaccine targets, as they are commonly elicited during infection. Understanding the interplay between viral evolution and the development of these antibodies provides insights that may guide immunogen design. Our work contrasted the dynamics of the early strain-specific antibodies and the later broadly neutralizing responses to a common Env target (V3C3), showing slower and more complex escape from bNAbs. Constrained bNAb escape, together with evidence of contemporaneous autologous virus neutralization, supports the proposal that prolonged exposure of the bNAb epitope enabled the maturation of the bNAb lineage.