Critical domains for HIV-1 entry through atypical coreceptor usage

通过非典型辅助受体使用进入 HIV-1 的关键领域

基本信息

批准号：
8712360
负责人：
FENG GAO
金额：
$ 19.63万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-05 至 2016-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The great majority of HIV-1 strains enter CD4+ target cells by interacting with one of two coreceptors, CCR5 and CXCR4. It has been considered that alternative coreceptors are not been used for primary clinical infection. However, we recently discovered a transmitted/founder (T/F) virus (ZP6248) that was profoundly impaired in its ability to utilize CCR5 and CXCR4 coreceptors on multiple CD4+ cell lines as well as primary human CD4+ T cells and macrophages in vitro, yet replicated to a high plasma viral load during acute infection. In contrast to all other T/F viruses that invariably use CCR5 as a coreceptor, ZP6248 uses the coreceptor GPR15 most efficiently in in vitro assays. A single mutation (E314G) in the rare V3 crown tip of ZP6248 restored its infectivity in CCR5+ cells, but reduced its ability to replicate in GPR15+ cells. Introduction of glutamic acid at this same position in other virus backbones leads to significant alterations of coreceptor usage, but does not render them infectious in GPR15+ cells. This is the first case demonstrating that HIV-1 can use coreceptors other than CCR5 and CXCR4 to establish clinical infection. Thus, it will be important to understand what are the mechanisms involved in establishing a primary HIV-1 infection in humans without the use of CCR5 or CXCR4 as coreceptors. In addition, it is striking that a single amino acid substitution at the V3 crown tip leads to significantly altered coreceptor usage in different virus backbones. These findings provide a unique model to study the precise interactions between the V3 crown tip and various coreceptors. Thus, we will use this unique virus as a model to address the following fundamental biological questions that are critical for understanding of coreceptor tropism of this evolving viral pathogen: (i), what novel infection mechanisms are used by a transmitted HIV-1 variant with atypical coreceptor usage and what are the motifs in the envelope glycoprotein that govern the coreceptor tropism; (ii), how conformational changes caused by a single amino acid substitution in the V3 crown tip allows the virus to sample alternative coreceptors to establish clinical infection. This work is central t our understanding and anticipation of virus-host coevolution that will drive the future of the HIV-1 epidemic.

描述（由申请人提供）：绝大多数HIV-1菌株通过与CCR5和CXCR4的两个共肽之一相互作用，进入CD4+目标细胞。人们认为，替代的共感染者未用于原发性临床感染。但是，我们最近发现了一种传播/创始人（T/F）病毒（ZP6248），该病毒在多个CD4+细胞系上利用CCR5和CXCR4共肽的能力严重损害，以及在高血浆病毒期间的替代性中，在多个CD4+细胞系中以及替代的原发性CD4+ T细胞和巨噬细胞。与所有其他使用CCR5用作共肽的T/F病毒相反，ZP6248在体外测定中最有效地使用Corecector GPR15。 ZP6248稀有V3冠尖的单个突变（E314G）恢复了其在CCR5+细胞中的感染性，但降低了其在GPR15+细胞中复制的能力。在其他病毒骨架中的同一位置引入谷氨酸会导致共受体使用的显着改变，但不会使它们在GPR15+细胞中具有感染性。这是第一种情况，表明HIV-1可以使用除CCR5和CXCR4以外的其他共感受器来建立临床感染。因此，重要的是要了解在不使用CCR5或CXCR4作为共肽器的情况下，在人类中建立原发性HIV-1感染的机制是什么。此外，令人惊讶的是，V3冠尖的单个氨基酸取代会导致不同病毒骨架中的共肽使用情况发生了显着改变。这些发现提供了一个独特的模型，可以研究V3冠尖与各种共感受器之间的精确相互作用。因此，我们将使用这种独特的病毒作为模型来解决以下基本的生物学问题，这些问题对于理解这种不断发展的病毒病原体的共感受器的端主是至关重要的：（i），透射的HIV-1变体与非典型的共核能使用及什么是corecoproterist corcoptorrist corcecoptors condersift; （ii），V3冠尖中的单个氨基酸取代引起的构象变化如何使病毒采样替代的共核能建立临床感染。这项工作是我们对病毒宿主共同进化的理解和预期，这将推动HIV-1流行的未来。