Effects of lymphoid tissue stromal cells on cell-to-cell HIV-1 spread

 描述(申请人提供)：HIV-1，艾滋病的病原体，通过细胞间传播比通过无细胞感染更有效地传播到T细胞。在基于组织培养的研究中，HIV-1感染的T细胞和未感染的目标T细胞形成被称为病毒学突触(VS)的细胞接触结构，在那里可能发生大规模的病毒转移。然而，在淋巴组织中细胞间传播的性质仍鲜为人知，在淋巴组织中，接触介导的病毒传播可能是有利的。细胞间的病毒传播不仅可以有效地传播HIV-1，而且被证明可以帮助HIV-1逃避体液免疫反应和一些抗病毒药物的效果。此外，在淋巴器官环境中，HIV-1感染的T细胞向不允许的静息T细胞进行细胞间传播会导致流产感染，从而导致静息T细胞的大量死亡。此外，在基质细胞产生的淋巴组织趋化因子存在的情况下，感染静止的T细胞会导致病毒潜伏。因此，充分阐明促进细胞间传播的机制，特别是在淋巴组织环境中，对于我们理解HIV-1的发病机制是至关重要的。淋巴组织的T细胞区除了含有T细胞和抗原提呈细胞外，还含有基质细胞。这些基质细胞形成密集的网络，对T细胞的相互作用和运输起结构和调节作用。尽管T细胞区基质细胞对T细胞行为的影响已变得明确，但这些基质细胞在HIV-1传播中所起的作用尚不确定，部分原因是缺乏易于处理的模型系统。值得注意的是，我们的初步数据表明，共培养系统中基质细胞的存在改变了细胞间HIV-1传播的效率。基于这些观察，我们假设淋巴组织基质细胞促进了HIV-1在细胞间的传播，从而促进了病毒的繁殖、潜伏期或细胞死亡。为了解决这一假设，在这一探索性拨款申请中，我们计划[1]确定基质细胞对VS形成和细胞间的影响 [2]阐明基质细胞在感染静息T细胞和随后导致潜伏期和/或细胞死亡的过程中所起的作用。在这些研究中，将使用新开发的共培养系统来检查细胞接触的特性、病毒传播的性质以及感染细胞的命运，这些系统模拟了T细胞区的环境。这些研究旨在填补我们在理解艾滋病毒-1在淋巴器官中传播方面的知识空白。他们还有望为该领域提供一个模型系统，在该系统中，病毒的传播和受感染细胞的命运可以在生理上相关但易于处理的环境中进行分析。

 DESCRIPTION (provided by applicant): HIV-1, the causative agent of AIDS, spreads to T cells much more efficiently via cell-to-cell transmission than via cell-free infection. In tissue-culture-based studies, HIV-1-infected T cells and uninfected target T cells form cell contact structures known as the virological synapses (VS) at which massive virus transfer is likely to take place. However, the nature of cell-to-cell transmission in the context of lymphoid tissues where the contact-mediated virus spread is likely favored remains poorly understood. Cell-to-cell virus transmission is not only efficient in spreading HIV-1 but also shown to help HIV-1 to evade humoral immune response and effects of a few antivirals. Furthermore, in lymphoid organ environment, cell-to-cell transmission from HIV-1-infected T cells to non-permissive resting T cells causes abortive infection, which leads to massive death of the resting T cells. In addition, infection of resting T cells in the presence of lymphoid tissue chemokines produced by stromal cells leads to viral latency. Therefore, fully elucidating the mechanisms promoting cell-to-cell transmission, especially in lymphoid tissue environment, is critical for our understanding of HIV-1 pathogenesis. T cell zones of lymphoid tissues contain stromal cells in addition to T cells and antigen-presenting cells. These stromal cells form a dense network and play structural and regulatory roles for T cell interactions and trafficking. Although the effects of the T cell zone stromal cells on T cell behaviors have become clear, the role played by these stromal cells in HIV-1 spread is undetermined, partly due to the lack of tractable model systems. Notably, our preliminary data suggest that the presence of stromal cells in a coculture system alters the efficiency of cell-to-cell HIV-1 spread. Based on these observations, we hypothesize that lymphoid tissue stromal cells facilitates cell-to-cell HIV-1 spread and thereby promotes viral propagation, latency or cell death. To address this hypothesis, in this exploratory grant application, we plan [1] to determine the effects of stromal cells on VS formation and cell-to-cell HIV-1 transmission and [2] to elucidate roles played by stromal cells in infection of resting T cells and subsequent processes leading to latency and/or cell death. In these studies, the properties of cell contacts, the nature of virus spread, and the fates of infected cells will be examined using newly developed coculture systems, which model the T cell zone environment. These studies are designed to fill the knowledge gaps in our understanding of HIV-1 spread in lymphoid organs. They are also expected to provide the field with a model system in which virus spread and fates of infected cells can be analyzed in a physiologically relevant yet tractable environment.