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

FRC 在 HIV-1 传播和潜伏期建立中的作用

• 批准号: 10759591
• 负责人: Tomoyuki Murakami
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759591
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Architecture; B-Lymphocytes; CD4 Positive T Lymphocytes; CD44 gene; Cell Separation; Cells; Coculture Techniques; Development; Environment; Follicular Dendritic Cells; Goals; HIV; HIV Infections; HIV-1; HIV/AIDS; Helper-Inducer T-Lymphocyte; Human; Hyaluronan; Infection; Investigation; Ligands; Lymphocyte; Macaca mulatta; Mediating; Memory; Organ; Outcome; Outcome Study; Pathogenesis; Patients; Play; Polysaccharides; Predisposition; Prevention strategy; Process; Productivity; Proliferating; Property; Proteins; Research; Rest; Reticular Cell; Rhesus; Role; SIV; Site; Source; Study models; System; T-Lymphocyte; Testing; Viral reservoir; Virion; Virus Latency; Work; antiretroviral therapy; cell motility; chemokine; cytokine; enhancing factor; experimental study; in vivo; latent infection; lymph nodes; permissiveness; prevent; secondary lymphoid organ; transcriptome; transcriptome sequencing; virtual

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.

包括淋巴结（LNS）在内的继发性淋巴机构是HIV-1扩散的主要部位。此外， 次生淋巴机构含有病毒储存剂，这是固化辅助设备的障碍。滤泡辅助T细胞 B细胞卵泡中的卵泡树突状细胞被充分研究为LNS中的病毒储层。值得注意的是，除了B LN中的细胞卵泡，T细胞区域（TCZ）包含抗逆转录病毒中的真正和持续病毒储存 治疗抑制的HIV-1患者。然而，尽管TCZ可能是病毒储存的来源，但如何 HIV-1传播以及如何在TCZ中产生病毒储存库的理解不足。在此应用程序中 我们建议确定TCZ成纤维细胞网状细胞（TRC）对HIV-1和SIV扩散以及潜伏期的影响 建立。我们先前证明了从人类LNS分离的TRC介导HIV的转染 - 1，透明质酸（多糖）和CD44之间的相互作用在此过程中起关键作用。 此外，我们的初步实验表明，TRC呈现静止的CD4+ T细胞，最丰富的细胞 TCZ中的组，当T细胞与TRC先前共培养时，允许生产和潜在感染 感染。因此，静止的CD4+ T细胞和TRC之间的相互作用可能促进HIV- 1通过两种机制传播，即增强HIV-1感染和介导转染的允许性。 但是，尚不清楚TRC是否介导HIV-1通过CD44-羟基龙相互作用的转染 体内以及TRC如何增强静息CD4+ T细胞对生产性和潜在感染的允许性。我们 将研究从猕猴LNS中分离的TRC是否通过CD44-介导SIV的转染。 透明质酸相互作用在体内。这项调查使我们能够确定跨性别的保护程度 上述感染机制以及体内SIV/恒河猕猴模型的有用性 TRC依赖性HIV-1在次级淋巴器官中扩散。此外，我们将确定TRC因素 使静止的CD4+ T细胞允许感染HIV-1并定义TRC在潜伏期中的作用 在TCZS中建立。拟议研究的完成建立了机械的基础 了解TRC在HIV传播和潜伏期中的作用，并可能有助于发展 抑制潜伏期的策略。