Host Genetics Core

CHAVI应用的总体目标是阐明HIV-1的病毒和宿主决定因素 在人类原发感染中的传播、持久性和部分遏制，并将这些发现转化为合理的疫苗设计。Core A将通过在宿主基因组学和HIV-1遗传学领域提供专业知识和服务来支持这一努力。核心由三个部分组成： 1.宿主基因组学科(在David Goldstein博士的领导下)将阐明宿主遗传差异对艾滋病毒-1感染的易感性和艾滋病毒-1感染早期疾病进展的影响。具体任务包括(1)确定、验证500个高优先级人类基因的可靠标记SNPs(TSNPs)并进行分型，以促进间接遗传关联研究；(Ii)确定直接关联研究候选基因中的假定功能变异；(Iii)制定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)在遗传和功能水平上调查所有关联；以及(Vi)建立一个强大的临床及宿主和病毒遗传数据管理系统。 2.艾滋病毒-1分子生物学和测序科(在比阿特丽斯·哈恩博士的领导下)将从急性和慢性感染者中产生有功能的艾滋病毒-1包膜克隆和全长艾滋病毒-1序列，以阐明性传播病毒的遗传、生物学、抗原性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感染的功能性包膜基因；(Ii)检查来自急性和慢性HIV-1感染的包膜的表型差异；以及(Iii)从急性HIV-1感染的患者那里获得全长HIV-1序列。 3.艾滋病毒-1计算生物学和生物统计科(由贝特·科伯领导)将提供交互式自动艾滋病毒-1序列录入和分析工具，并建立和维护一个急性艾滋病毒-1序列数据库。具体任务包括：(I)提供交互式自动HIV-1序列数据输入系统，使用户能够识别测序错误和污染，作为其初始数据处理的一部分；(Ii)提供交互式自动化工具，用于CHAVI HIV-1序列的基线分析/，(Iii)公开CHAVI HIV-1序列，(Iv)建立CHAVI调查员接口，用于免疫学数据输入，(V)分析急性感染序列的HIV-1序列数据集 签名和(Vi)为CHAVI的努力提供统计支持。在2002年，这些部分中的每一个都将成为一个独立的核心设施(见战略计划)，与宿主和艾滋病毒-1序列分析的预期增加相称。

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.