Mechanisms Underlying Persistent Lentivirus Replication in Follicular T Cells

滤泡 T 细胞中慢病毒持续复制的机制

• 批准号: 8466682
• 负责人: Elizabeth Connick
• 金额: $ 69.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466682
• 关键词: Acute; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; BLR1 gene; Binding; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Maturation; Cell Separation; Cells; Cessation of life; Chronic; Chronic Disease; Complex; Cytotoxic T-Lymphocytes; Development; Follicular Dendritic Cells; Fostering; Frequencies; HIV; HIV-1; Helper-Inducer T-Lymphocyte; Human; In Situ; In Situ Hybridization; In Vitro; Individual; Infection; Label; Lead; Lentivirus Infections; Location; Lymphocyte Function; Lymphoid Tissue; Macaca; Macaca mulatta; Measures; Minority; Modeling; Phenotype; Predisposition; Reporter; Role; SIV; Series; Signal Transduction; Sorting - Cell Movement; Staining method; Stains; Structure of germinal center of lymph node; Subfamily lentivirinae; T-Cell Immunodeficiency; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tissues; Vaccines; Virion; Virus; Virus Replication; adaptive immunity; cytokine; in vitro Assay; in vivo; permissiveness; public health relevance; research study; therapeutic target; viral RNA

DESCRIPTION (provided by applicant): In both chronic HIV-1 and SIV infection, virus replication is concentrated in lymphoid tissues in follicular CD4+ T cells, which are 30 to 40 times more likely to be productively infected than extrafollicular CD4+ T cells. Reasons why lentiviruses are preferentially replicated by follicular CD4+ T cells and why virus-specific cytotoxic T lymphocytes (CTL) cannot suppress replication in these cells are not understood. Virus replication is not concentrated in B cell follicles in acute SIV infection, suggesting that te follicular concentration of virus may be related to adaptive immunity. T follicular helper cells (TFH) are a specialized subset of antigen-specific cells that migrate into B cell follicles where they interact with B cells and follicular dendritic cells (FDC) to promote B cell maturation and antibody production. We hypothesize that virus replication is concentrated within TFH in chronic HIV-1 and SIV infection due to 1) increased intrinsic susceptibility of TFH to productive lentiviru infection, 2) their location in germinal centers (GC) adjacent to antibody-virion complexes on FDC, and 3) numerical and functional deficiencies of follicular CTL. These hypotheses will be tested through a series of experiments both in vitro and in vivo using lymphoid tissues from humans and rhesus macaques. In Aim 1, we will establish whether human and macaque TFH are intrinsically more susceptible to productive lentivirus infection than other CD4+ T cells through in vitro experimental infections with GFP reporter viruses. In aim 2, we will determine the distribution and phenotype of productively infected T cells in vivo in both chronic and acute lentivirus infection by in situ tissue analyses as well as measuring viral RNA in sorted subsets of cells. In Aim 3 we will investigate the hypothesis that numerical and/or functional deficiencies in follicular CTL contribute to the propagation of HIV-1 within B cell follicles using in situ studies in vitro assays of follicular CTL function, and CD8 depletion of rhesus macaques in vivo. In the context of all aims, we will evaluate the impact of T follicular regulatory cells (TFR), on HIV-1 replication and CTL function. Collectively, these studies will provide a wealth of new information on the cells that foster HIV-1 replication in B cell follicles and factors in the follicular milieuthat may promote or impair lentivirus replication. A better understanding of the mechanisms that underlie permissiveness of follicular CD4+ T cells to lentiviruses is vital to development of a protective vaccine or a functional cure for HIV-1.

描述(申请人提供)：在慢性HIV-1和SIV感染中，病毒复制集中在滤泡CD4+T细胞中的淋巴组织中，这些细胞被生产性感染的可能性是滤泡外CD4+T细胞的30到40倍。为什么慢病毒优先由滤泡CD4+T细胞复制，以及为什么病毒特异性细胞毒性T淋巴细胞(CTL)不能抑制这些细胞的复制，目前尚不清楚。急性SIV感染时B细胞滤泡病毒复制不集中，提示滤泡病毒浓度可能与获得性免疫有关。T滤泡辅助细胞(TFH)是一种特殊的抗原特异性细胞亚群，它们迁移到B细胞滤泡中，在那里它们与B细胞和滤泡树突状细胞(FDC)相互作用，促进B细胞成熟和抗体产生。我们推测，在慢性HIV-1和SIV感染中，病毒复制集中在TFH内，原因是1)TFH对生产性慢病毒感染的内在易感性增加，2)它们位于FDC上靠近抗体-病毒复合体的生发中心(GC)，以及3)滤泡CTL数量和功能缺陷。这些假说将通过使用人类和猕猴的淋巴组织进行一系列体外和体内实验来验证。在目标1中，我们将通过体外实验感染GFP报告病毒来确定人类和猕猴TFH是否比其他CD4+T细胞更容易受到生产性慢病毒的感染。在目标2中，我们将通过原位组织分析和测量病毒分类亚群中的病毒RNA来确定在慢性和急性慢病毒感染中体内可产生感染的T细胞的分布和表型。 细胞。在目标3中，我们将调查这样的假设，即数字和/或功能缺陷 通过对滤泡CTL功能和体内恒河猴CD8耗竭的原位研究表明，滤泡CTL有助于HIV-1在B细胞滤泡内的繁殖。在所有目标的背景下，我们将评估T滤泡调节细胞(TFR)对HIV-1复制和CTL功能的影响。总而言之，这些研究将提供大量关于B细胞毛囊中促进HIV-1复制的细胞和毛囊环境中可能促进或损害慢病毒复制的因素的新信息。更好地了解滤泡CD4+T细胞对慢病毒的透过性机制，对于开发保护性疫苗或HIV-1的功能性治疗至关重要。