Analysis of HIV acquisition via the ovary

通过卵巢感染艾滋病毒的分析

• 批准号: 8732374
• 负责人: Daniel John Stieh
• 金额: $ 5.15万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732374
• 关键词: Address; Anatomic Sites; Animals; Anti-Retroviral Agents; Antiviral Agents; Area; Attention; CD4 Positive T Lymphocytes; Cells; Chronic; Data; Development; Endometrium; Environment; Epithelial; Epithelium; Event; Female; Flow Cytometry; Fluorescence Microscopy; Goals; HIV; HIV Infections; HIV-1; Heterosexuals; Human; Human Biology; Immune; Infection; Knowledge; Lead; Left; Lentivirus Vector; Light; Local Microbicides; Luciferases; Macaca; Macaca mulatta; Microscopic; Microscopy; Modality; Modeling; Monitor; Monkeys; Mucous Membrane; Mucous body substance; Oral Administration; Outcome; Ovarian Tissue; Ovary; Pharmaceutical Preparations; Phenotype; Predisposition; Prevention; Process; Relative (related person); Reporter; Reporting; Research; Research Personnel; SIV; Seminal fluid; Series; Simple Columnar Epithelium; Site; Sterility; System; Techniques; Tissue Model; Tissues; Training; Tropism; Uterus; Vaccines; Vagina; Viral; Virion; Virus; Virus Diseases; Woman; Work; cell type; efficacy trial; experience; human tissue; in vivo; innovation; male; novel; protein expression; public health relevance; receptor; reproductive; research study; transmission process

DESCRIPTION (provided by applicant): Annually, more than two million new HIV infections occur worldwide, with the largest proportion of new infections occurring in women through heterosexual intercourse. Considerable attention has been given to understanding the initial events following viral acquisition in the female reproductive tract, however infection throughout the upper reproductive tract has not been reported. Infection is initiated after virions cross the mucus barriers coating the reproductive tract and the epithelial layers to access target cells. The process of HIV-1 transmission has been thought to occur at specific sites. A focus has been on vulnerability of simple columnar epithelium covered endocervical tissue as being especially susceptible. Recent findings by our research team have explored the entirety of the FRT and bring this into question. We find that all areas where virus can cross mucosal barriers are able to be infected with the transmitting inoculum. These findings were made possible by the development of a novel dual reporter lentiviral vector which allows identification of infected tissue at a macroscopic level by luciferase expression as well as at the single cell level by fluorescent reporter expression. Because mucosal barriers are generally effective that spread of infection is an inefficient process. Therefore, it is the goal of this proposal to further elucidat the mechanisms by which transmission occurs, with a specific focus on the upper female reproductive tract. Ex vivo human tissue models and the in vivo Rhesus Macaque SIV challenge model will be used to study the target cells and early infection events after HIV or SIV acquisition. This analysis will use fluorescence microscopy analysis of healthy and infected tissues to describe the immunological environment and how it changes after viral challenge. The experiments proposed in Aim 1 will establish foundational knowledge of the immune cells present in human and monkey ovarian tissue where infection can occur, and compare this to uterine tissue where we have not found evidence of infection. These studies will lead to a better understanding of where preventative antiviral mechanisms such as vaccines need to be poised to act. The outcomes should provide a framework for understanding the vulnerability of ovarian tissue to HIV transmission in women. In Aim 2, the process of viral spread and the feasibility of ovarian tissue supporting sustained infection will be examined using replicating virus infection alongside reporter virus. In Aim 3, the monkey challenge model will be used to determine the effect of changes in viral envelope from chronic to transmitted/founder types which have been implicated as being uniquely suited for initiating infection. In summary, these studies seek to provide a better understanding of the process of viral transmission, specific to the upper FRT, and the importance of target cells and viral envelope determinants to initiate infection.

描述（由申请人提供）：每年，全世界都有超过200万种新的艾滋病毒感染，新的感染最大的新感染发生在女性中，通过异性恋性交发生。人们非常关注女性生殖道中的病毒释放后的初始事件，但是尚未报道整个上层生殖道的感染。在病毒体横穿粘液层覆盖生殖道和上皮层以访问靶细胞的粘液屏障之后，开始感染。这 人们认为HIV-1传输过程在特定地点发生。重点是简单的柱状上皮覆盖核心组织的脆弱性，因为它特别容易受到敏感。我们的研究团队的最新发现探索了整个FRT，并质疑这一点。我们发现，所有病毒都可以跨粘膜屏障的地区能够感染传播接种物。这些发现是通过开发新的双重报道慢病毒载体的发展，该载体可以通过荧光素酶表达以及通过荧光报告基因表达来鉴定受感染的组织。因为粘膜屏障通常是有效的，因此感染传播是一个效率低下的过程。因此，该提案的目的是进一步阐明传播发生的机制，并特别关注上部女性生殖道。体内人体组织模型和体内恒河猕猴SIV挑战模型将用于研究艾滋病毒或艾滋病毒后的靶细胞和早期感染事件。该分析将使用对健康和感染组织的荧光显微镜分析来描述免疫学环境以及病毒挑战后其如何变化。 AIM 1中提出的实验将建立可能发生感染的人和猴子卵巢组织中存在的免疫细胞的基础知识，并将其与我们没有发现感染证据的子宫组织进行比较。这些研究将使人们更好地理解预防性抗病毒机制（例如疫苗）需要采取行动。结果应提供一个框架，以了解卵巢​​组织对女性艾滋病毒传播的脆弱性。在AIM 2中，将使用与记者病毒一起复制病毒感染来检查病毒扩散的过程和支持持续感染的卵巢组织的可行性。在AIM 3中，猴子挑战模型将用于确定病毒膜从慢性变化到传播/创始人类型的变化的影响，这些变化被暗示为非常适合发起感染。总而言之，这些研究试图更好地了解特有上FRT的病毒传播过程，以及靶细胞和病毒包膜决定因素启动感染的重要性。