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

 描述（由申请人提供）：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细胞和未感染的靶T细胞形成细胞接触结构，称为病毒学突触（VS），大规模病毒转移可能发生。然而，在接触介导的病毒传播可能有利的淋巴组织中，细胞间传播的性质仍然知之甚少。细胞间病毒传播不仅能有效传播HIV-1，而且还能帮助HIV-1逃避体液免疫反应和一些抗病毒药物的作用。此外，在淋巴器官环境中，从HIV-1感染的T细胞到非允许性静息T细胞的细胞间传播导致感染失败，这导致静息T细胞的大量死亡。此外，在存在由基质细胞产生的淋巴组织趋化因子的情况下，静息T细胞的感染导致病毒潜伏。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的发病机制至关重要。淋巴组织的T细胞区除了T细胞和抗原呈递细胞外，还含有基质细胞。这些基质细胞形成密集的网络，并在T细胞相互作用和运输中发挥结构和调节作用。虽然T细胞区基质细胞对T细胞行为的影响已经变得清楚，但这些基质细胞在HIV-1传播中所起的作用尚未确定，部分原因是缺乏易处理的模型系统。值得注意的是，我们的初步数据表明，基质细胞在共培养系统中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细胞间HIV-1传播，从而促进病毒繁殖、潜伏或细胞死亡。为了解决这一假设，在这个探索性的拨款申请中，我们计划[1]确定基质细胞对VS形成和细胞对细胞的影响。 HIV-1传播和[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，细胞接触的性质，病毒传播的性质，以及受感染细胞的命运将使用新开发的共培养系统进行检查，该系统模拟T细胞区环境。这些研究旨在填补我们对HIV-1在淋巴器官中传播的认识空白。他们还有望为该领域提供一个模型系统，其中可以在生理相关但易于处理的环境中分析病毒传播和受感染细胞的命运。

 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.