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.

该CHAVI应用程序的总体目标是阐明HIV-1的病毒和宿主决定因素 传播，持久性和部分遏制原发性人类感染，并将这些发现转化为合理的疫苗设计。核心A将通过在宿主基因组学和HIV-1遗传学领域提供专门知识和服务来支持这一努力。核心部分由三个部分组成： 1.宿主基因组学部分（在大卫戈尔茨坦博士的领导下）将阐明宿主遗传差异影响对HIV-1感染的易感性和早期HIV-1感染的疾病进展。具体任务包括：（i）鉴定、验证和基因分型一组用于500个高优先级人类基因的标签SNP（tSNP），以促进间接遗传关联研究;（ii）鉴定候选基因中用于直接关联研究的推定功能变体;（iii）开发统一的实验基因分型方法;（iv）优化用于恒河猴直接关联研究的测序引物;（v）调查遗传和功能水平上的所有关联;以及（vi）建立一个强大的数据管理系统，用于临床以及宿主和病毒遗传数据。 2. HIV-1分子生物学和测序部分（在Beatrice Hahn博士的领导下）将从急性和慢性感染者中产生功能性HIV-1 env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、克隆和测序急性HIV-1感染的功能性env基因;（ii）检查急性和慢性HIV-1感染的包膜表型差异;（iii）从急性HIV-1感染患者中获得全长HIV-1序列。 3. HIV-1计算生物学和生物统计学科（由Bette Korber领导）将提供交互式自动HIV-1序列输入和分析工具，并建立和维持急性HIV-1序列数据库。具体任务包括：㈠提供一个交互式自动HIV-1序列数据输入系统，使用户能够在其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）建立CHAVI研究者界面用于免疫学数据的数据输入，（V）分析HIV-1序列数据集的急性感染序列 签名和（六）为CHAVI工作提供统计支持。在2002年，这些部门中的每一个都将成为一个独立的核心设施（见战略计划），与宿主和HIV-1序列分析的预期增长相称。