Host Genetics Core

宿主遗传学核心

• 批准号: 8294660
• 负责人: NORMAN L LETVIN
• 金额: $ 134.08万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294660
• 关键词: AIDS/HIV problem; Acute; Affect; Area; Biometry; Candidate Disease Gene; Characteristics; Chronic; Clinical; Computational Biology; Containment; Core Facility; Data; Data Set; Databases; Disease Progression; Genes; Genetic; Genomics; Genotype; Goals; HIV-1; Human; Immunology; Individual; Infection; Leadership; Length; Macaca mulatta; Molecular Biology; Patients; Predisposition; Research Personnel; Sequence Analysis; Services; Strategic Planning; System; Translating; Vaccine Design; Vaccines; Variant; Viral; Virus; computerized data processing; data management; env Genes; genetic association; tool; transmission process; virus genetics

The overall goal of this CHAVI application is to elucidate viral and host determinants of HIV-1 transmission, persistence, and partial containment in primary human infection, and to translate these findings into rational vaccine design. Core A will support this effort by providing expertise and service in the areas of host genomics and HIV-1 genetics. The Core is comprised of three sections: 1. The Host Genomics Section (under the leadership of Dr. David Goldstein) will elucidate host genetic differences affecting susceptibility to HIV-1 infection and disease progression in early HIV-1 infection. Specific tasks include to (i) identify, validate, and genotype a robust set of tagging SNPs (tSNPs) for 500 high priority human genes to facilitate indirect genetic association studies, (ii) identify putative functional variants among the candidate genes for direct association studies; (iii) develop uniform experimental genotyping approaches; (ivj optimize sequencing primers for direct association studies in the rhesus monkey; (v) investigate all associations at the genetic and functional level; and (vi) establish a robust data management system for clinical as well as host and viral genetic data. 2. The HIV-1 Molecular Biology and Sequencing Section (under the leadership of Dr. Beatrice Hahn), will generate functional HIV-1 env clones and full-length HIV-1 sequences from acutely and chronically infected individuals to elucidate the genetic, biologic, antigenic, and structural characteristics of sexually transmitted virus and the mechanisms underlying this transmission. Specific tasks include to (i) amplify, clone and sequence functional env genes from acute HIV-1 infections; (ii) examine envelopes from acute and chronic HIV-1 infections for phenotypic differences, and (iii) derive full-length HIV-1 sequences from patients with acute HIV-1 infection. 3. The HIV-1 Computational Biology and Biostatistics Section (under the leadership of Bette Korber), will provide interactive automated HIV-1 sequence entry and analysis tools, and establish and maintain an Acute HIV-1 Sequence Database. Specific tasks include to (i) provide an interactive automated HIV-1 sequence data entry system that enables users to identify sequencing errors and contamination as part of their initial data processing; (ii) provide interactive automated tools for baseline analysis/of CHAVI HIV-1 sequences, (iii) make CHAVI HIV-1 sequences publicly available, (iv) build CHAVI investigator interfaces for data entry of immunological data, (v) analyze HIV-1 sequence datasets for acute infection sequence signatures and (vi) provide statistical support for the CHAVI effort. In Year 02, each of these sections will become an independent core facility (see Strategic Plan), commensurate with the anticipated increase of both host and HIV-1 sequence analysis.

CHAVI 应用的总体目标是阐明 HIV-1 的病毒和宿主决定因素 人类原发感染的传播、持久性和部分遏制，并将这些发现转化为合理的疫苗设计。核心 A 将通过提供宿主基因组学和 HIV-1 遗传学领域的专业知识和服务来支持这一努力。核心由三个部分组成： 1. 宿主基因组学部分（由 David Goldstein 博士领导）将阐明影响 HIV-1 感染易感性和早期 HIV-1 感染疾病进展的宿主遗传差异。具体任务包括 (i) 识别、验证 500 个高优先级人类基因的一组强大的标记 SNP (tSNP) 并进行基因分型，以促进间接遗传关联研究，(ii) 识别候选基因中假定的功能变异以进行直接关联研究； (iii) 开发统一的实验基因分型方法； (iv) 优化恒河猴直接关联研究的测序引物；(v) 研究遗传和功能水平的所有关联；(vi) 为临床以及宿主和病毒遗传数据建立强大的数据管理系统。 2. HIV-1分子生物学和测序部分（由Beatrice Hahn博士领导）将从急性和慢性感染个体中产生功能性HIV-1包膜克隆和全长HIV-1序列，以阐明性传播病毒的遗传、生物学、抗原和结构特征以及这种传播的机制。具体任务包括 (i) 扩增、克隆急性 HIV-1 感染的功能性 env 基因并对其进行测序； (ii) 检查急性和慢性 HIV-1 感染的包膜的表型差异，以及 (iii) 从急性 HIV-1 感染患者获得全长 HIV-1 序列。 3. HIV-1计算生物学和生物统计学科（在Bette Korber的领导下）将提供交互式自动化HIV-1序列输入和分析工具，并建立和维护急性HIV-1序列数据库。具体任务包括 (i) 提供交互式自动化 HIV-1 序列数据输入系统，使用户能够在初始数据处理过程中识别测序错误和污染； (ii) 提供用于 CHAVI HIV-1 序列基线分析的交互式自动化工具，(iii) 公开 CHAVI HIV-1 序列，(iv) 构建用于免疫数据输入的 CHAVI 研究人员界面，(v) 分析急性感染序列的 HIV-1 序列数据集 (vi) 为 CHAVI 工作提供统计支持。在第 02 年，这些部分中的每一个都将成为一个独立的核心设施（参见战略计划），与宿主和 HIV-1 序列分析的预期增长相称。