Molecular Evolution of HIV Clade C Env in Two Species

有效的HIV-1疫苗的开发一直受到快速突变和基因突变的阻碍。 在整个病毒基因组中的变异，特别是env基因。在这份提案中，我们试图分析 围产期感染的儿童中HIV进化枝C env基因的进化。同时，我们将分析 恒河猴感染SHIV毒株后env基因的进化 C env基因。我们假设两个不同物种的env基因的分子进化 遵循相似的模式。与核心A一起，我们将产生编码env基因的新SHIV毒株 来自艾滋病毒C分支感染的赞比亚婴儿，艾滋病毒疾病进展迅速。我们假设Env是 致病性的决定因素，这将反映在相应的SHIV株在猕猴。的 项目1的总体目标是确定非人灵长类动物感染SHIV和 其中env的最终分子进化是研究人类HIV-1进化的合适模型。 我们的近期目标是纵向分离围产期感染婴儿的样本， 进化枝C env基因的模式和宿主内多样性。使用病毒的核苷酸序列数据 从受感染的人和猕猴中平行获得的分离株，我们将测试几种假设， 遗传多样性、疾病进展和临床表型之间的关系。这项建议会 利用一个正在进行的研究项目，研究艾滋病毒和其他病毒的围产期传播， 来自赞比亚的母婴对。具体目标是： 1)为了表征在不同时间点从婴儿中分离的HIV-1进化枝C的Env蛋白的变化， 疾病进程，并将这些变化与疾病进展相关联。 2)为了表征SHIV C进化枝的Env蛋白，在感染者的病程中纵向分离， 动物，并将这些变化与动物和患者的疾病进展相关联。 3)为了表征从配对患者中获得的病毒的Env蛋白的生物学特性， 猕猴与时间的关系，并将这些变化与疾病进展相关联。 这项研究将提供重要的预测信息，艾滋病毒进化支C的相关性， 与发病机制和疾病进展的env演变模式。这项研究也将带来更好的 了解疾病过程中宿主与病毒的相互作用，并将提供有用的信息， 设计疫苗

The development of an effective HIV-1 vaccine has been hampered by the rapid rate of mutation and genetic variation throughout the viral genome, especially the env gene. In this proposal, we seek to analyze the evolution of HIV clade C env genes in children that were perinatally infected. In parallel, we will analyze the evolution of env genes in rhesus monkeys infected with SHIV strains encoding the corresponding HIV clade C env genes. We hypothesize that the molecular evolution of env genes in the two different species will follow similar patterns. Together with Core A, we will generate new SHIV strains that encode env genes from HIV clade C-infected Zambian infants with rapid HIV disease progression. We hypothesize that Env is a determinant for pathogenicity, which will be mirrored in the corresponding SHIV strains in macaques. The overall objective of Project 1 is to determine whether infection of non-human primates by SHIV and the resultant molecular evolution of env therein, is a suitable model for studying HIV-1 evolution in humans. Our immediate goal is to longitudinally isolate samples from perinatally infected infants and to characterize the patterns and within-host diversification of clade C env genes. Using nucleotide sequence data from viral isolates obtained in parallel from infected humans and macaques, we will test several hypotheses regarding the relationships among genetic diversity, disease progression, and clinical phenotypes. This proposal will make use of an ongoing research project to study perinatal transmission of HIV and other viruses in mother/infant pairs (MIPs) from Zambia. The Specific Aims are: 1) To characterize changes in Env proteins of HIV-1 clade C isolated from infants at different time points in the disease course, and correlate these changes to disease progression. 2) To characterize Env proteins of SHIV clade C isolated longitudinally over the disease course in infected animals, and correlate these changes to disease progression in both the animals and the patients. 3) To characterize the biological properties of Env proteins of viruses obtained from the paired patients and macaques with time, and correlate these changes to disease progression. This study will provide important predictive information about the evolution of HIV clade C by correlating patterns of env evolution with pathogenesis and disease progression. This study will also lead to a better understanding of the host-virus interaction during the disease course and will provide useful information for designing vaccines.