LONGITUDINAL ANALYSIS OF HIV-1 CLADE C FITNESS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 C亚型人类免疫缺陷病毒1型(HIV-1)占全球艾滋病毒-1新感染病例的56%以上，包括艾滋病毒-1从受感染的妇女传播给她们的孩子。HIV的包膜糖蛋白通过受体相互作用确定细胞的亲和性，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，关于环境病毒进化、病毒适合性、传播和疾病进展之间的关系还知之甚少。假设HIV-1的适合性与环境属性相关，并随着环境的变化而纵向进化，高适合性病毒优先从母亲传播给婴儿，在那里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的疾病进展中的作用，以及它与环境病毒序列变化的关系。我们之前已经纵向描述了来自赞比亚卢萨卡的7名C亚型HIV-1围产期感染儿童的HIV-1包膜基因的演变。我们已经创建了包含C亚型env序列的前病毒和env表达载体，这些序列来自HIV-1分支B(NL4-3)主干中的这些母婴对。我们现在已经利用得到的嵌合体来测试Env的处理、Env介导的融合、融入病毒颗粒、病毒复制动力学、中和敏感性和复制能力/适合性，并确定了与这些感染儿童的围产期传播或疾病进展相关的包膜的特殊特征。

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. Subtype C human immunodeficiency virus type 1 (HIV-1) accounts for over 56% of HIV-1 new infections globally, including the transmission of HIV-1 from infected women to their children. 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 seven 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. We have now utilized the resulting chimeras to test Env processing, Env mediated fusion, incorporation into viral particles, viral replication kinetics, neutralization sensitivity and replication capacity/fitness and determined the particular characteristics of the envelope that are correlated with perinatal transmission or disease progression in these infected children.