Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, United States.
Monogram Biosciences, South San Francisco, CA, United States.
Front Immunol. 2019 May 15;10:1021. doi: 10.3389/fimmu.2019.01021. eCollection 2019.
Although it is now possible to produce recombinant HIV envelope glycoproteins (Envs) with epitopes recognized by the 5-6 major classes of broadly neutralizing antibodies (bNAbs), these have failed to consistently stimulate the formation of bNAbs in immunized animals or humans. In an effort to identify new immunogens better able to elicit bNAbs, we are studying Envs derived from rare individuals who possess bNAbs and are able to control their infection without the need for anti-retroviral drugs (elite supressors or ES), hypothesizing that in at least some people the antibodies may mediate durable virus control. Because virus evolution in people with the ES only phenotype was reported to be limited, we reasoned the Env proteins recovered from these individuals may more closely resemble the Envs that gave rise to bNAbs compared to the highly diverse viruses isolated from normal progressors. Using a phenotypic assay, we screened 25 controllers and identified two for more detailed investigation. In this study, we examined 20 clade B proviral sequences isolated from an African American woman, who had the rare bNAb/ES phenotype. Phylogenetic analysis of proviral envelope sequences demonstrated low genetic diversity. Envelope proteins were unusual in that most possessed two extra cysteines within an elongated V1 region. In this report, we examine the impact of the extra cysteines on the binding to bNAbs, virus infectivity, and sensitivity to neutralization. These data suggest structural motifs in V1 can affect infectivity, and that rare viruses may be prevented from developing escape.
虽然现在可以生产具有 5-6 种主要广谱中和抗体 (bNAb) 识别表位的重组 HIV 包膜糖蛋白 (Env)，但这些糖蛋白未能在免疫动物或人体中持续刺激 bNAb 的形成。为了寻找能够更好地引发 bNAb 的新免疫原，我们正在研究来自具有 bNAb 且能够在无需抗逆转录病毒药物的情况下控制感染的罕见个体的 Envs，假设至少在某些人中，抗体可能介导持久的病毒控制。由于报道具有 ES 单一表型的个体中的病毒进化受到限制，我们推断从这些个体中回收的 Env 蛋白可能与从正常进展者中分离出的高度多样化病毒相比，更接近引发 bNAb 的 Envs。使用表型测定法，我们筛选了 25 名控制器，并确定了两名进行更详细的研究。在这项研究中，我们检查了从一名具有罕见 bNAb/ES 表型的非裔美国女性中分离出的 20 个 clade B 前病毒序列。前病毒包膜序列的系统发育分析表明遗传多样性低。包膜蛋白异常，大多数在伸长的 V1 区域内有两个额外的半胱氨酸。在本报告中，我们研究了额外半胱氨酸对 bNAb 结合、病毒感染力和中和敏感性的影响。这些数据表明 V1 中的结构基序会影响感染力，并且罕见病毒可能会防止发生逃逸。
