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: 8113111
• 负责人: DONALD E MOSIER
• 金额: $ 50.04万
• 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/8113111
• 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; 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. PUBLIC HEALTH RELEVANCE (provided by applicant): HIV-1 is a rapidly mutating virus, and infected individuals may contain more than a million different mutated viruses within one year of infection, however, transmission to another individual usually involves only one of these many different viruses. We will use examples of these recently transmitted founder viruses to define the properties that distinguish the rare, sexually transmissible virus from the vastly larger number of viruses that are not transmitted. This information is essential for designing strategies to prevent transmission.

描述（由申请人提供）：HIV-1 的传播是一种罕见的事件，涉及从受感染捐赠者的多达 1 亿个基因型中极端、非随机地选择最少一个创始基因型。这项研究计划的目的是了解为什么传播具有如此选择性，以及什么生物学特性定义了这种罕见的、高度传播的病毒。使用来自 4 种 C 亚型原发感染和 1 种 B 亚型感染的创始病毒的感染性分子克隆，为区分少数高度传染性病毒和许多非传染性病毒提供了关键资源。该研究计划有两个具体目标。第一个是使用 Transwell 培养物模拟 HIV 体外传播，其中病毒必须穿过完整的上皮屏障才能到达靶细胞。病毒添加条件和可用靶细胞都会发生变化，以模拟粘膜传播的自然位点和驻留的 CD4+ T 细胞靶标。所测试的假设是，高度传播的病毒必须能够有效地穿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，以区分容易传播的病毒和传播性差的病毒。在第二个具体目标中，将通过创建具有最佳传播性的 HIV-1 包膜的猿猴-人类免疫缺陷病毒包膜嵌合体来测试体外模型的结果，并使用所得的 SHIV 在恒河猴中进行阴道激发研究。在体外和体内研究中，对高传染性病毒与低传染性病毒的基因型和生物学特性的广泛分析将有助于定义决定传播成功的特征。因此，该研究计划的最终产品将是更好地了解 HIV-1 传播，以及反映创始病毒而不是晚期分离株的一种或多种 SHIV 嵌合病毒，并将为临床前预防研究提供更相关的试剂。 公共卫生相关性（由申请人提供）：HIV-1 是一种快速变异的病毒，感染者在感染后一年内可能含有超过一百万种不同的变异病毒，然而，传播给另一个人通常只涉及这多种不同病毒中的一种。我们将使用这些最近传播的创始人病毒的示例来定义将罕见的性传播病毒与大量非传播病毒区分开来的特性。这些信息对于设计预防传播的策略至关重要。