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HIV-1现在是世界上含量最多、发展最快的亚型。HIV-1的包膜糖蛋白是病毒亲和性(受体识别)和病毒进入时病毒与细胞膜融合的主要决定因素。HIV-1的传播依赖于包膜糖蛋白的受体结合和融合功能。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。我们最近纵向描述了赞比亚卢萨卡7名临床结局不同的C亚型HIV-1围产期感染儿童的HIV-1包膜基因的演变。我们发现病毒多样性与感染时间相关，目前正在从这七对受感染的母婴中构建不同的前病毒和环境表达结构。正在对这些嵌合体进行病毒学表征，以确定是否存在与C亚型HIV-1围产期传播或受感染儿童的疾病进展相关的特定的Env生物决定因素/功能(融合、病毒进入、复制动力学、中和敏感性和复制能力/适合度)。

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 HIV-1 is now the most abundant and the most rapidly expanding subtype in the world. The envelope (Env) glycoprotein of HIV-1 is the primary determinant of viral tropism (receptor recognition) and fusion of viral and cellular membrane in viral entry. HIV-1 transmission is dependent on receptor binding and fusion functions of the envelope glycoprotein. 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 recently 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 found that viral diversity correlates with time of infection and are now in the process of constructing different proviral and Env expression constructs from these seven infected mother/ infant pairs. These chimeras are being characterized virologically to determine whether there are specific biological determinants/ functions of Env (fusion, virus entry, replication kinetics, neutralization sensitivity and replication capacity/fitness) that correlate with subtype C HIV-1 perinatal transmission or disease progression in infected children.