Modeling HIV-1 primary transmission in vitro and in vivo

HIV-1 初次传播的体外和体内建模

• 批准号: 8434156
• 负责人: DONALD E MOSIER
• 金额: $ 56.45万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-07 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434156
• 关键词: Animals; Biological; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Characteristics; Chimera organism; Collaborations; Dose; Epithelial; Epithelial Cells; Event; Failure; Genetic; Genital system; Genome; Genotype; Goals; HIV; HIV-1; In Vitro; Individual; Infection; Label; Laminin; Macaca; Macaca mulatta; Modeling; Molecular Cloning; Mutate; Nuclear Pore Complex; Peptides; Phenotype; Physiological; Population Heterogeneity; Prevention; Prevention strategy; Progestins; Property; Reagent; Reporting; Research; Research Proposals; Resources; Rest; SIV; Seminal Plasma; Sexual Transmission; Simulate; Staging; Submucosa; System; Testing; Tissues; Toxic effect; Vagina; Variant; Virus; design; in vitro Model; in vivo; macrophage; microbicide; monolayer; mucosal site; pre-clinical; preclinical evaluation; prevent; programs; public health relevance; research study; simian human immunodeficiency virus; success; transcytosis; transmission process; virus culture; virus envelope

DESCRIPTION (provided by applicant): Transmission of HIV-1 is a rare event that involves extreme, non-random selection of as few as one founder genotype out of as many as 100 million genotypes in the infected donor. The goal of this research proposal is to understand why transmission is so selective, and what biological properties define the rare, highly transmissible virus. The use of infectious molecular clones of founder viruses from 4 subtype C primary infections and 1 subtype B infection provides a key resource to distinguish the few highly transmissible viruses from the many non-transmissible viruses. The research proposal has two specific aims. The first is to model HIV transmission in vitro using transwell cultures where virus must cross an intact epithelial barrier to reach target cells. Both the conditions of virus addition and the available target cells will be varied to mimic the natural sites of mucosal transmission and the resident CD4+ T cell targets. The hypothesis under test is that a highly transmissible virus must be able to both cross the epithelial cell barrier efficiently and infect the first available target cell efficiently, and that these two properties can be modeled in vitro to distinguish readily transmissible viruses from poorly transmissible viruses. In the second specific aim, the results of the in vitro model will be put to the test by creating a simian-human immunodeficiency virus envelope chimera with the best transmitted HIV-1 envelope, and using the resulting SHIV for vaginal challenge studies in rhesus macaques. In both in vitro and in vivo studies, extensive analysis of the genotypic and biological properties of highly transmissible versus poorly transmissible viruses will allow the definition of the characteristics that define transmission success. The end product of this research program will thus be a better understanding of HIV-1 transmission, and one or more SHIV chimeric viruses that reflect founder viruses rather than late-stage isolates, and will provide a much more relevant reagent for preclinical prevention studies.

描述（由申请人提供）：HIV-1的传播是一个罕见的事件，涉及极端的非随机选择，仅在受感染供体中多达1亿个基因型中的创始人基因型少于创始人的基因型。该研究建议的目的是了解传播是如此选择性的原因，以及哪些生物学特性定义了罕见的，高度可传播的病毒。从4种亚型C原发性感染和1个亚型B感染中使用感染性病毒的传染性分子克隆提供了一种关键资源，可以将少数高度可传播病毒与许多不可传播的病毒区分开。研究建议有两个具体的目标。首先是使用Transwell培养物在体外对HIV传播进行建模，其中病毒必须越过完整的上皮屏障才能到达目标细胞。添加病毒的条件和可用靶细胞的条件都将变化，以模仿粘膜传播的自然部位和驻留的CD4+ T细胞靶标。正在检验的假设是，高度可传播的病毒必须能够有效地越过上皮细胞屏障并有效地感染第一个可用的靶细胞，并且可以在体外对这两种特性进行建模，以区分易于传播的病毒与不良的传播病毒。在第二个特定目的中，将通过创建具有最佳传播HIV-1信封的猿类免疫缺陷病毒包膜嵌合体来进行体外模型的结果，并在恒河猕猴中使用所得的SHIV进行阴道挑战研究。在体外和体内研究中，对高度可传播和可传播病毒的基因型和生物学特性的广泛分析将允许定义定义传播成功的特征。因此，该研究计划的最终产物将是对HIV-1传播的更好理解，一种或多种反映创始人病毒而不是晚期分离株的SHIV嵌合病毒，并将为临床前预防研究提供更相关的试剂。