LONGITUDINAL ANALYSIS OF HIV-1 CLADE C FITNESS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 HIV-1亚型C是目前全球绝大多数新的HIV-1感染的原因。HIV的包膜糖蛋白通过受体相互作用确定细胞向性，并介导病毒与靶细胞的融合，在确定传播性方面发挥主要作用。然而，在儿童C亚型的背景下，对Env进化、病毒适应性、传播和疾病进展之间的关系知之甚少。该假说是HIV-1适应性与Env特性相关，并随着Env的变化纵向进化，并且高适应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感染儿童疾病进展中的作用，以及它与Env序列变化的关系。我们以前纵向特点的演变，HIV-1包膜基因从一组C亚型HIV-1围产期感染的儿童与不同的临床结果，从赞比亚卢萨卡。我们已经创建了前病毒和Env表达构建体，其含有在HIV-1进化枝B（NL 4 -3）骨架中衍生自这些母婴对的亚型C Env序列。此外，我们利用所得嵌合体来确定是否有特定的生物决定因素/功能的Env（加工，Env介导的融合，纳入病毒颗粒，病毒复制动力学，中和敏感性和复制健身），与亚型C HIV-1围产期传播或疾病进展，在这些感染的儿童。

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.