Viral Characteristics Associated with the Clinical Nonprogressor Phenotype Are Inherited by Viruses from a Cluster of HIV-1 Elite Controllers
Viral Characteristics Associated with the Clinical Nonprogressor Phenotype Are Inherited by Viruses from a Cluster of HIV-1 Elite Controllers
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DOI：
10.1128/mbio.02338-17
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发表时间：
2018-03-01
期刊：
影响因子：
6.4
通讯作者：
Lopez-Galindez, Cecilio
中科院分区：
文献类型：
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作者：
Casado, Concepcion;Marrero-Hernandez, Sara;Lopez-Galindez, Cecilio
一小群HIV-1感染者，称为长期无进展者（LTNP），特别是LTNP的一个亚组，精英控制者（LTNP-EC），显示出对病毒复制的永久控制和缺乏临床进展。这种控制是宿主、免疫和病毒因素复杂相互作用的结果。我们确定，通过系统发育分析，一组LTNP-EC感染非常相似的低复制HIV-1病毒，表明共同的病毒特征的临床LTNP-EC表型的贡献。HIV-1包膜糖蛋白（Env）介导信号传导并促进HIV-1融合、进入和感染，是病毒体外适应性、细胞病变和体内感染进展的关键因素。因此，我们从这些患者的病毒和慢性感染的对照个体中分离出全长env基因。病毒感染初始事件的功能表征表明，与慢性患者的Envs相比，LTNP-EC的Envs在与CD 4的结合以及肌动蛋白/微管蛋白细胞骨架修饰的关键触发方面无效。簇病毒的病毒特性导致有缺陷的病毒融合、进入和感染，并且这些特性被簇中的每个病毒继承。因此，低效的HIV-1 Env功能和信号传导缺陷可能导致簇集病毒的低病毒复制能力和传播性，这表明在这些个体的LTNP-EC表型中起直接作用。这些结果突出了病毒特征在LTNP-EC临床表型中的重要作用。这些Env病毒的特性是共同的所有簇病毒，从而支持的遗传性的病毒characteristics.IMPORTANCE HIV-1长期nonprogressor精英控制患者，由于他们的永久控制病毒复制，一直是许多研究的对象，以确定负责这种临床表型的因素。在这项工作中，我们分析了病毒的包膜的病毒特性从LTNP-EC患者的系统发生簇。这些包膜表现出与CD 4的无效结合以及随后修饰肌动蛋白/微管蛋白细胞骨架的信号传导活性，这导致低融合和缺乏进入和感染能力。这些Env病毒特征可以解释这些患者的非进展临床表型。此外，这些低效的env病毒特性存在于簇的所有病毒中，支持病毒表型的遗传性。
A small group of HIV-1-infected individuals, called long-term nonprogressors (LTNPs), and in particular a subgroup of LTNPs, elite controllers (LTNP-ECs), display permanent control of viral replication and lack of clinical progression. This control is the result of a complex interaction of host, immune, and viral factors. We identified, by phylogenetic analysis, a cluster of LTNP-ECs infected with very similar low-replication HIV-1 viruses, suggesting the contribution of common viral features to the clinical LTNP-EC phenotype. HIV-1 envelope (Env) glycoprotein mediates signaling and promotes HIV-1 fusion, entry, and infection, being a key factor of viral fitness in vitro, cytopathicity, and infection progression in vivo. Therefore, we isolated full-length env genes from viruses of these patients and from chronically infected control individuals. Functional characterization of the initial events of the viral infection showed that Envs from the LTNP-ECs were ineffective in the binding to CD4 and in the key triggering of actin/tubulin-cytoskeleton modifications compared to Envs from chronic patients. The viral properties of the cluster viruses result in a defective viral fusion, entry, and infection, and these properties were inherited by every virus of the cluster. Therefore, inefficient HIV-1 Env functions and signaling defects may contribute to the low viral replication capacity and transmissibility of the cluster viruses, suggesting a direct role in the LTNP-EC phenotype of these individuals. These results highlight the important role of viral characteristics in the LTNP-EC clinical phenotype. These Env viral properties were common to all the cluster viruses and thus support the heritability of the viral characteristics.IMPORTANCE HIV-1 long-term nonprogressor elite controller patients, due to their permanent control of viral replication, have been the object of numerous studies to identify the factors responsible for this clinical phenotype. In this work, we analyzed the viral characteristics of the envelopes of viruses from a phylogenetic cluster of LTNP-EC patients. These envelopes showed ineffective binding to CD4 and the subsequent signaling activity to modify actin/tubulin cytoskeletons, which result in low fusion and deficient entry and infection capacities. These Env viral characteristics could explain the nonprogressor clinical phenotype of these patients. In addition, these inefficient env viral properties were present in all viruses of the cluster, supporting the heritability of the viral phenotype.