LONGITUDINAL ANALYSIS OF HIV-1 CLADE C FITNESS

HIV-1 C 类适应性的纵向分析

• 批准号: 7959389
• 负责人: HONG ZHANG
• 金额: $ 17.07万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959389
• 关键词: Biological; Cells; Cellular Tropism; Child; Chimera organism; Clinical; Computer Retrieval of Information on Scientific Projects Database; Disease Progression; Evolution; Funding; Genes; Glycoproteins; Grant; HIV; HIV-1; Infant; Infection; Institution; Kinetics; Mediating; Mothers; Nebraska; Outcome; Perinatal; Play; Process; Property; Research; Research Personnel; Resources; Role; Source; United States National Institutes of Health; Vertebral column; Vertical Disease Transmission; Viral; Virus; Zambia; fitness; longitudinal analysis; particle; receptor; transmission process; virology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV-1 subtype C is currently responsible for the vast majority of new HIV-1 infections worldwide. The envelope glycoprotein of HIV plays the primary role in determining transmissibility by defining cellular tropism through receptor interactions, and by mediating fusion of virus to target cells. Yet very little is known about the relationships between Env evolution, viral fitness, transmission, and disease progression, in the context of subtype C in children. The hypothesis is that HIV-1 fitness correlates with Env properties and evolves longitudinally with changes in the Env, and that high fitness viruses are preferentially transmitted from mothers to infants where they mediate more rapid disease progression. The overall objective is to determine the role of viral envelope in mother to child transmission and disease progression in the infected children, and how it relates to changes in the Env sequences. We have previously longitudinally characterized the evolution of the HIV-1 envelope gene from a panel of subtype C HIV-1 perinatally infected children with different clinical outcomes from Lusaka, Zambia. We have created proviral and Env expression constructs containing subtype C Env sequences derived from these mother-infant pairs in an HIV-1 clade B (NL4-3) backbone. In addition, we have utilized the resulting chimeras to determine whether there are specific biological determinants/ functions of Env (processing, Env mediated fusion, incorporation into viral particles, viral replication kinetics, neutralization sensitivity and replication fitness ) that correlate with subtype C HIV-1 perinatal transmission or disease progression in these infected children.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 目前，全球绝大多数新发 HIV-1 感染都是由 HIV-1 C 亚型引起的。 HIV 的包膜糖蛋白通过受体相互作用定义细胞向性，并介导病毒与靶细胞的融合，在决定传播性方面发挥着主要作用。然而，在儿童 C 亚型的背景下，人们对环境进化、病毒适应性、传播和疾病进展之间的关系知之甚少。该假设认为，HIV-1 适应性与 Env 特性相关，并随着 Env 的变化而纵向进化，并且高适应性病毒优先从母亲传播到婴儿，在婴儿中它们介导更快的疾病进展。总体目标是确定病毒包膜在母婴传播和受感染儿童疾病进展中的作用，以及它与包膜序列变化的关系。我们之前纵向描述了来自赞比亚卢萨卡的一组 C 亚型 HIV-1 围产期感染儿童的 HIV-1 包膜基因的进化，这些儿童具有不同的临床结果。我们创建了原病毒和 Env 表达构建体，其中包含源自 HIV-1 进化枝 B (NL4-3) 主链中这些母婴对的 C 亚型 Env 序列。此外，我们利用所得的嵌合体来确定是否存在与 C 亚型 HIV-相关的特定的 Env 生物决定因素/功能（加工、Env 介导的融合、掺入病毒颗粒、病毒复制动力学、中和敏感性和复制适应性）。 1 这些受感染儿童的围产期传播或疾病进展。