The roles of FRCs in HIV-1 spread and establishment of latency

次级淋巴器官包括淋巴结(LNS)是HIV-1传播的主要部位。此外， 次级淋巴器官含有病毒库，这是治愈艾滋病的障碍。滤泡辅助性T细胞 而B细胞滤泡中的滤泡树突状细胞在LNS中作为病毒储存库被研究得很好。值得注意的是，除了B LN内的细胞滤泡、T细胞区(TCZ)包含真正的潜伏和持久的抗逆转录病毒储存库 治疗抑制的HIV-1患者。然而，尽管TCZ有可能成为病毒库的来源，但如何 HIV-1病毒的传播以及TCZ中的病毒库是如何产生的，人们知之甚少。在此应用程序中， 我们建议确定TCZ成纤维细胞网状细胞(TrCs)对HIV-1和SIV传播和潜伏期的影响 建制派。我们先前证明，从人类LNS分离的TRCs介导HIV-1的反式感染。 透明质酸(一种多糖)与CD44之间的相互作用在这一过程中起着关键作用。 此外，我们的初步实验表明，TRCs产生静息的CD4T细胞，这是最丰富的细胞 TCZ中的群体，当T细胞与TRCs事先共培养时，允许生殖性感染和潜伏感染 与感染有关。因此，静息的CD4T细胞和TRCs之间的相互作用可能促进HIV- 1通过两种机制传播，即增强对艾滋病毒-1感染的允许性和中介转染性。 然而，目前尚不清楚trc是否通过CD44-透明质酸相互作用来介导HIV-1的反式感染。 以及TRCs如何增强静止的CD4T细胞对生产性和潜伏性感染的抵抗力。我们 将研究从恒河猴LNS分离的TRCs是否通过CD44-介导SIV的反式感染 透明质酸体外相互作用。这项调查使我们能够确定反式- 上述感染机制及SIV/恒河猴体内模型研究的有效性 依赖TRC的HIV-1在次级淋巴器官扩散。此外，我们将确定TRC因素 这使得静息的CD4T细胞对HIV-1感染是允许的，并定义了TRCs在潜伏期中的作用 在TCZ设立。拟议研究的完成奠定了机械论的基础 了解区域控制中心在艾滋病毒传播和潜伏期中的作用，并可有助于发展 抑制潜伏期建立的策略。

Secondary lymphoid organs including lymph nodes (LNs) are a major site for HIV-1 spread. Furthermore, secondary lymphoid organs harbor viral reservoirs, which are a barrier to curing AIDS. Follicular helper T cells and follicular dendritic cells in B cell follicles are well studied as viral reservoirs in LNs. Notably, in addition to B cell follicles, T cell zones (TCZs) within LNs contain bona fide latent and persistent viral reservoirs in antiretroviral therapy-suppressed HIV-1 patients. However, despite the potential of TCZs as a source of viral reservoirs, how HIV-1 disseminates and how viral reservoirs are generated in TCZs are poorly understood. In this application, we propose to determine the effect of TCZ fibroblastic reticular cells (TRCs) on HIV-1 and SIV spread and latency establishment. We previously demonstrated that TRCs isolated from human LNs mediate trans-infection of HIV- 1 and that the interaction between hyaluronan (a polysaccharide) and CD44 plays a key role in this process. Additionally, our preliminary experiments showed that TRCs render resting CD4+ T cells, the most abundant cell group in TCZs, permissive to both productive and latent infection when the T cells are cocultured with TRCs prior to infection. Therefore, it is possible that the interactions between resting CD4+ T cells and TRCs promote HIV- 1 spread by two mechanisms, i.e., enhancing of permissiveness to HIV-1 infection and mediating trans-infection. However, it is unknown whether TRCs mediate trans-infection of HIV-1 through CD44-hyaluronan interactions in vivo and how TRCs enhance the permissiveness of resting CD4+ T cells to productive and latent infection. We will investigate whether TRCs isolated from rhesus macaque LNs mediate trans-infection of SIV via CD44- hyaluronan interactions ex vivo. This investigation allows us to determine the extent of conservation of the trans- infection mechanism described above and the usefulness of an in vivo SIV/rhesus macaque model for studies of TRC-dependent HIV-1 spread in secondary lymphoid organs. Additionally, we will identify the TRC factors that render resting CD4+ T cells permissive to HIV-1 infection and define the roles of TRCs in latency establishment in TCZs. Completion of the proposed research establishes the basis for a mechanistic understanding of the roles of TRCs in HIV dissemination and latency and could contribute to the development of a strategy inhibiting latency establishment.