The Early Events Determining SIV Rectal Transmission

决定 SIV 直肠传播的早期事件

• 批准号: 8310089
• 负责人: Qingsheng Li
• 金额: $ 29.55万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8310089
• 关键词: Address; Anatomy; Anus; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cervical; Cervix Uteri; Colon; Dendritic Cells; Development; Distal; Effector Cell; Event; HIV-1; Host Defense; Immune response; Immune system; In Situ; In Situ Hybridization; Infection; Inflammation; Intervention; Knowledge; Lamina Propria; Lead; Local Microbicides; Location; Lymphoid; Lymphoid Tissue; Macaca mulatta; Modeling; Physiological; Play; Procedures; Public Health; Race; Rectum; Research; Role; SIV; Site; Spatial Distribution; Systemic infection; T-Lymphocyte; Testing; Time; Tissues; Vaccines; Vagina; Virus; Virus Replication; cell type; design; innovation; insight; macrophage; men who have sex with men; microbicide; novel; prevent; rectal; response; spatial relationship; transmission process; vaginal transmission

Although anal intercourse is a common mode of HIV-1 transmission, particularly for men who have sex with men, many fundamental and mechanistic questions remain. The long-term objective of this study is to understand the early events in HIV-1 rectal transmission and to gain new insights, which will potentially lead to new intervention strategies, including vaccines and topical microbicides optimized for rectal use. Studying HIV-1 vaginal transmission in the highly relevant SIV-rhesus macaque model has revealed important events critical for transmission, such as target cell availability, innate immune response, and inflammation at the portal of entry, all factors which play a key role in transmission. Because the anatomical/histological features and the physiological functions of vagina and cervix differ from the rectum, we hypothesize that the underlying mechanisms and timing of HIV-1 rectal transmission will significantly differ from those of vaginal-cervical transmission. Utilizing innovative approaches and an established conceptual framework from studies of vaginal transmission, we will test this hypothesis by investigating three specific aims: 1) determine the timing, location, spatial distribution and cell types of virus-infected cells at the portal of entry and in draining and distal lymphatic tissues; 2) determine relationships between virus and susceptible target cells (CD4+ T cells, macrophages, and dendritic cells) and between virus-infected cells and the mucosal innate immune response in the rectum shortly after intra-rectal SIV inoculation, thereby determining whether changes in target-cell availability play a critical role in local expansion and systemic spread of infection; and 3) determine the spatial relationships and ratio of virus-specific CD8+ T effector cells (E) and virus-infected-target cells (T) at the portal of entry and in other tissue compartments to extent of control of virus replication, using a novel procedure combining in-situ tetramers and in-situ hybridization The proposed research is significant as it is expected to reveal important mechanisms underlying rectal transmission and potentially provide guidance for designing anti-HIV-1 vaccines and topical microbicides.

尽管肛交是 HIV-1 传播的常见方式，特别是对于男男性行为者，但许多基本和机制问题仍然存在。这项研究的长期目标是了解 HIV-1 直肠传播的早期事件并获得新的见解，这将有可能导致新的干预策略，包括针对直肠使用优化的疫苗和外用杀菌剂。在高度相关的 SIV-恒河猴模型中研究 HIV-1 阴道传播，揭示了对传播至关重要的重要事件，例如靶细胞可用性、先天免疫反应和进入门户的炎症，所有因素在传播中发挥关键作用。由于阴道和宫颈的解剖/组织学特征和生理功能与直肠不同，我们假设 HIV-1 直肠传播的基本机制和时间将与阴道-宫颈传播显着不同。利用创新方法和阴道传播研究中建立的概念框架，我们将通过研究三个具体目标来检验这一假设：1）确定病毒感染细胞在进入入口和进入的时间、位置、空间分布和细胞类型。引流和远端淋巴组织； 2）直肠内SIV接种后不久，确定病毒与易感靶细胞（CD4+ T细胞、巨噬细胞和树突状细胞）之间以及病毒感染细胞与直肠粘膜先天免疫反应之间的关系，从而确定靶细胞是否发生变化-细胞可用性在感染的局部扩张和全身传播中发挥着关键作用； 3) 使用结合原位四聚体和原位杂交的新方法这项研究具有重要意义，因为它有望揭示直肠传播的重要机制，并可能为设计抗 HIV-1 疫苗和局部杀菌剂提供指导。