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: 8238279
• 负责人: DONALD E MOSIER
• 金额: $ 49.54万
• 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/8238279
• 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. 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，涉及从受感染供体的多达1亿种基因型中极端、非随机选择少至一种创始基因型。这项研究计划的目标是了解为什么传播是如此具有选择性，以及什么生物学特性定义了这种罕见的高传染性病毒。使用来自4种亚型C初次感染和1种亚型B感染的创始病毒的感染性分子克隆提供了区分少数高度传播性病毒与许多非传播性病毒的关键资源。研究计划有两个具体目标。第一种是使用transwell培养物在体外模拟HIV传播，其中病毒必须穿过完整的上皮屏障才能到达靶细胞。病毒添加的条件和可用的靶细胞都将变化，以模拟粘膜传播的天然位点和固有的CD 4 + T细胞靶标。测试的假设是，高传播性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，并且这两个特性可以在体外建模以区分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的HIV-1包膜的猿猴-人免疫缺陷病毒包膜嵌合体，并将所得SHIV用于恒河猴的阴道攻击研究，来测试体外模型的结果。在体外和体内研究中，对高传播性病毒与低传播性病毒的基因型和生物学特性进行广泛分析，将有助于确定传播成功的特征。因此，这项研究计划的最终产品将更好地了解HIV-1传播，以及一种或多种反映创始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。 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100多万种不同的变异病毒，然而，传播给另一个人通常只涉及这些不同病毒中的一种。我们将使用这些最近传播的创始人病毒的例子来定义将罕见的性传播病毒与大量不传播的病毒区分开来的特性。这些信息对于制定预防传播的战略至关重要。