The Early Events Determining SIV Rectal Transmission

虽然肛交是一种常见的HIV-1传播方式，尤其是对男男性行为者来说，但仍然存在许多根本性和机械性的问题。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，这可能会导致新的干预策略，包括优化直肠使用的疫苗和局部杀微生物剂。在高度相关的SIV-恒河猴模型中对HIV-1阴道传播的研究揭示了对传播至关重要的重要事件，如靶细胞可获得性、先天免疫反应和进入入口的炎症，所有这些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，我们推测HIV-1直肠传播的潜在机制和时间将显著不同于阴道-宫颈传播。利用创新的方法和已建立的阴道传播研究的概念框架，我们将通过调查三个具体目标来检验这一假说：1)确定病毒感染细胞在入口以及引流和远端淋巴组织中的时间、位置、空间分布和细胞类型；2)确定病毒与易感靶细胞(CD4T细胞、巨噬细胞和树突状细胞)之间的关系，以及病毒感染细胞与直肠粘膜先天免疫反应之间的关系，从而确定靶细胞可用性的变化是否在感染的局部扩张和全身扩散中起关键作用；3)利用原位四聚体和原位杂交相结合的新方法，确定病毒特异性CD8T效应细胞(E)和病毒感染靶细胞(T)在入口处和其他组织间的空间关系和比率，以控制病毒复制。该研究具有重要意义，因为它有望揭示直肠传播的重要机制，并可能为抗HIV-1疫苗和局部杀微生物剂的设计提供指导。

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.