Molecular Evolution of HIV Clade C Env in Two Species

有效的HIV-1疫苗的开发一直受到突变和基因突变速度过快的阻碍 病毒基因组中的变异，尤其是env基因。在这项建议中，我们试图分析 围产期感染儿童HIV-C-env基因的演变同时，我们将分析 编码相应HIV亚型的新城疫病毒株感染恒河猴后env基因的进化 C env基因。我们假设在两个不同物种中env基因的分子进化将 遵循类似的模式。与核心A一起，我们将产生编码env基因的新的SHV毒株 来自艾滋病毒C分支感染的赞比亚婴儿，艾滋病毒疾病迅速发展。我们假设Env是 致病性的决定因素，这将反映在猕猴相应的希沃克病毒株中。这个 项目1的总体目标是确定新城疫病毒和沙门氏菌对非人类灵长类动物的感染 由此产生的包膜病毒的分子进化，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，并确定 Clade C env基因的模式和宿主内的多样性。使用来自病毒的核苷酸序列数据 从受感染的人和猕猴身上平行获得的分离株，我们将检验几个关于 遗传多样性、疾病进展和临床表型之间的关系。这项提议将 利用一个正在进行的研究项目，研究艾滋病毒和其他病毒在围产期的传播 赞比亚的母婴配对(MIP)。具体目标是： 1)分析婴幼儿HIV-1 C株不同时间点膜蛋白的变化。 病程，并将这些变化与疾病进展相关联。 2)对纵向分离的新城疫病毒C株包膜蛋白的特性进行了研究 并将这些变化与动物和患者的疾病进展相关联。 3)鉴定从配对患者中获得的病毒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的进展相关联。 这项研究将通过关联提供关于HIV C分支进化的重要预测信息 环境病毒的进化模式与发病机制和疾病进展。这项研究也将导致更好的 了解疾病过程中宿主与病毒的相互作用，将为 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.