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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毒株通过与两种辅助受体CCR5和CXCR4中的一种相互作用进入CD4+靶细胞。人们一直认为替代的辅助受体不用于原发性临床感染。然而，我们最近发现了一种传播/创建（T/F）病毒（ZP6248），该病毒在体外对多种CD4+细胞系以及原代人CD4+ T细胞和巨噬细胞利用CCR5和CXCR4辅助受体的能力严重受损，但在急性感染期间复制到高血浆病毒载量。与所有其他总是使用CCR5作为辅助受体的T/F病毒相比，ZP6248在体外试验中最有效地使用了辅助受体GPR15。ZP6248罕见的V3冠尖突变（E314G）恢复了其在CCR5+细胞中的感染性，但降低了其在GPR15+细胞中的复制能力。在其他病毒主干的同一位置引入谷氨酸会导致辅助受体使用的显著改变，但不会使它们在GPR15+细胞中具有传染性。这是第一个证明HIV-1可以使用CCR5和CXCR4以外的辅助受体建立临床感染的病例。因此，了解在不使用CCR5或CXCR4作为辅助受体的情况下在人类中建立原发HIV-1感染的机制是很重要的。此外，令人惊讶的是，V3冠尖端的单个氨基酸取代导致不同病毒主干中辅助受体使用的显着改变。这些发现为研究V3冠尖与各种共受体之间的精确相互作用提供了一个独特的模型。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生物学问题，这些问题对于理解这种不断进化的病毒病原体的共受体趋向性至关重要：(i)具有非典型共受体使用的传播HIV-1变体使用了哪些新的感染机制，以及包膜糖蛋白中控制共受体趋向性的基元是什么；（ii） V3冠端单个氨基酸取代引起的构象变化如何使病毒能够取样替代的辅助受体以建立临床感染。这项工作是我们对病毒-宿主共同进化的理解和预期的核心，这将推动HIV-1流行病的未来。