EARLY MECHANISMS OF HIV TRANSMISSION USING THE SIV/MACAQUE MODEL FOR AIDS

使用艾滋病病毒/猕猴模型研究艾滋病毒传播的早期机制

• 批准号: 8172686
• 负责人: Marie-Claire Elisabeth Gauduin
• 金额: $ 1.92万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172686
• 关键词: AIDS Vaccines; Accounting; Acquired Immunodeficiency Syndrome; CD4 Positive T Lymphocytes; Cells; Computer Retrieval of Information on Scientific Projects Database; Dendritic Cells; Development; Dissection; Epidemic; Funding; Generations; Genital system; Grant; HIV; Human; Immune response; Immunization; In Situ; Infection; Institution; Knowledge; Lymphocyte; Macaca; Macaca fascicularis; Methods; Modeling; Pathway interactions; Phenotype; Research; Research Personnel; Resources; SIV; Sexual Transmission; Site; Source; Sterility; Surface; Time; United States National Institutes of Health; Vaccines; Vagina; Viral; Virus Diseases; cell type; intraepithelial; macrophage; mucosal site; novel vaccines; prevent; rectal; success; transmission process; vaginal transmission

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sexual transmission of human immunodeficiency virus (HIV) accounts for the majority of new infections worldwide. A vaccine capable of preventing sexual transmission across genital or rectal mucosal surfaces could provide a method for stopping the AIDS epidemic. The ultimate success of strategies to prevent sexual transmission of HIV depends, in part, on a better understanding of the virological and immunological mechanisms that underlie sexual transmission. Numerous studies have demonstrated the difficulty to achieve sterile protection from vaginally or rectally acquired HIV/SIV using parenteral immunization. Mucosal immunization is seen as the best approach to achieve sustainable immune responses at mucosal sites of viral entry. Defining the mechanisms of vaginal HIV transmission, in particular the initial immune response is central to the development of effective strategies to develop a successful mucosal AIDS vaccine. Our knowledge of the initial target cells involved in mucosal transmission is still evolving. Increasing evidence suggests that the initial site of productive infection occurs in situ at the mucosal surface. Studies of vaginal transmission suggest that the potential initial target cell may be either activated CD4+ T cells or intraepithelial dendritic cells. Precise dissection of viral targets and pathways involved in sexual HIV transmission will prove essential to the global effort to develop a protective vaccine. The identification of initial target cells and the ability to elicit and to enhance cellular or humoral immune responses at mucosal sites is likely to be a crucial step in the development of novel vaccines. These questions are extremely difficult to pursue experimentally in humans. In this study we propose to examine in situ viral infection at mucosal portal of entry in the SIV/cynomolgus (Macaca fascicularis) macaque model using SIV tagged with GFP. Specific aims will include: 1) To identify the types of cells initially infected (i.e., lymphocytes, macrophages, and dendritic cells), their phenotype and function; 2) To investigate the mechanisms, time course, and pathways of viral spread from site of initial infection; and, 3) To explore generation of early mucosal cellular immune response at vaginal site of SIV infection.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 人类免疫缺陷病毒（HIV）的性传播占全球新增感染的大部分。一种能够防止通过生殖器或直肠粘膜表面进行性传播的疫苗可以提供一种阻止艾滋病流行的方法。预防艾滋病毒性传播策略的最终成功部分取决于对性传播背后的病毒学和免疫学机制的更好理解。大量研究表明，通过肠外免疫很难实现针对阴道或直肠感染 HIV/SIV 的无菌保护。粘膜免疫被视为在病毒进入粘膜部位实现可持续免疫反应的最佳方法。确定艾滋病毒阴道传播的机制，特别是初始免疫反应，对于制定成功的粘膜艾滋病疫苗的有效策略至关重要。我们对参与粘膜传播的初始靶细胞的了解仍在不断发展。越来越多的证据表明，生产性感染的初始部位发生在粘膜表面原位。阴道传播的研究表明，潜在的初始靶细胞可能是活化的 CD4+ T 细胞或上皮内树突状细胞。精确剖析涉及艾滋病毒性传播的病毒靶标和途径对于全球开发保护性疫苗的努力至关重要。初始靶细胞的识别以及在粘膜部位引发和增强细胞或体液免疫反应的能力可能是开发新型疫苗的关键步骤。这些问题在人类身上进行实验是极其困难的。在这项研究中，我们建议使用带有 GFP 标记的 SIV 来检查 SIV/食蟹猴（Macaca fasciculis）猕猴模型中粘膜入口处的原位病毒感染。 具体目标包括： 1) 确定最初感染的细胞类型（即淋巴细胞、巨噬细胞和树突状细胞）、它们的表型和功能； 2）研究病毒从初始感染部位传播的机制、时间过程和途径； 3) 探索 SIV 感染阴道部位早期粘膜细胞免疫反应的产生。