HIV induces Gli Proteins to skew naive CD4+ T cells to Th1 and TGF-b effectors

HIV 诱导 Gli 蛋白将幼稚 CD4 T 细胞偏向 Th1 和 TGF-b 效应细胞

• 批准号: 7760028
• 负责人: Christel H. Uittenbogaart
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760028
• 关键词: Antiviral Agents; Apoptosis; Apoptotic; Autoimmunity; Binding; Binding Sites; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Characteristics; Chronic; Communicable Diseases; Data; Disease; Down-Regulation; GLI Family Protein; GLI2 gene; Genes; Genetic Transcription; Glioma; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Human; Human T-lymphotropic virus 1; Immune; Immune system; Immunology; Immunosuppression; Immunosuppressive Agents; Infection; Inflammatory; Knowledge; Lead; Link; Malignant Neoplasms; Mediating; Multiple Sclerosis; Opportunistic Infections; Pathway interactions; Proteins; Role; T-Lymphocyte; Th1 Cells; Viral; Viral Pathogenesis; Viral Proteins; Virus; base; cell mediated immune response; cytokine; genetic regulatory protein; promoter; protein activation; public health relevance; response; tat Protein; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Generalized immune activation and apoptosis are key characteristics of progressive HIV-1 disease. HIV-1 Tat protein has been linked to skewing of naive T-cell differentiation and apoptosis; however, the exact mechanisms are not clearly defined. The GLI transcription factors are important regulatory proteins that are involved in cellular differentiation, proliferation, apoptosis, and gene transcription. We have discovered putative GLI binding sites in several pro-inflammatory and pro-apoptotic genes. Our proposal focuses on Tbx21 (Tbet) and TGF-21. Based on these data our overall hypothesis is that HIV-1 infection induces GLI protein activation to turn on immune specific genes that induce generalized immune activation and subsequent apoptosis. Furthermore, we hypothesize that HIV-1 Tat induces TGF-21 transcription by binding to GLI2 at the TGF-21 promoter. The goal of this proposal is to further elucidate the mechanisms whereby HIV-1 activates the human GLI transcription factors to induce transcription of genes responsible for immune activation and apoptosis. Specifically, we intend: 1. To elucidate the mechanisms by which HIV-1 modulates Gli transcription factors to induce Tbx21 (Tbet) gene leading to a pro-inflammatory Th1 response. 2. To investigate how HIV-1 Tat interacts with the cellular transcription factors GLI2/3 to induce the pleiotropic cytokine TGF-21, which can skew CD4+ T-cell differentiation and/or apoptosis. The answers to these questions will undoubtedly lead to increased knowledge of viral pathogenesis and general immunology. These unknown pathways would also be worthwhile therapeutic targets to disable the virus' ability to induce generalized immune activation and bystander apoptosis. The implications of understanding how TGF-21 is transcriptionally regulated are not exclusively pertinent to HIV-1 disease. This pleiotropic immunosuppressive and pro-apoptotic cytokine has key roles in other infectious diseases, autoimmunity, and cancer (HTLV-I, multiple sclerosis, gliomas, etc.). PUBLIC HEALTH RELEVANCE: Immune suppression is a key characteristic of progressive HIV-1 disease. The persistent down-regulation of antiviral cell-mediated responses and increase of immunoregulatory T-cells during chronic HIV infection disables the immune system's control over viral replication as well as opportunistic infections. The viral proteins HIV gp120 and Tat have been attributed to this immunosuppression, but the underlying mechanisms have not been clearly defined. We have recently found that the glioma (Gli) transcription factors are important in the induction the Tbet protein which is essential in cell-mediated immune response, and that HIV-1 inhibits Gli activity. The goal of this proposal is to further elucidate the mechanisms whereby HIV-1 modulates the human Gli transcription factors to skew T-cell differentiation away from antiviral Th1 cells toward immunosuppressive T-cells. The answers to these questions will undoubtedly lead to increased knowledge of viral pathogenesis and general immunology.

描述（由申请人提供）：全身免疫激活和细胞凋亡是进展性HIV-1疾病的关键特征。HIV-1 Tat蛋白与幼稚t细胞分化和凋亡的倾斜有关；然而，确切的机制还没有明确定义。GLI转录因子是参与细胞分化、增殖、凋亡和基因转录的重要调控蛋白。我们已经在几个促炎和促凋亡基因中发现了假定的GLI结合位点。我们的建议重点关注Tbx21 （Tbet）和TGF-21。基于这些数据，我们的总体假设是HIV-1感染诱导GLI蛋白激活，从而开启免疫特异性基因，从而诱导全身免疫激活和随后的细胞凋亡。此外，我们假设HIV-1 Tat通过与TGF-21启动子上的GLI2结合诱导TGF-21转录。本研究的目的是进一步阐明HIV-1激活人GLI转录因子诱导免疫激活和细胞凋亡相关基因转录的机制。具体地说，我们打算：阐明HIV-1通过调节Gli转录因子诱导Tbx21 （Tbet）基因导致促炎Th1反应的机制。2. 研究HIV-1 Tat如何与细胞转录因子GLI2/3相互作用，诱导多效性细胞因子TGF-21，从而扭曲CD4+ t细胞分化和/或凋亡。这些问题的答案无疑将导致对病毒发病机制和一般免疫学知识的增加。这些未知的途径也将是有价值的治疗靶点，以禁用病毒诱导全身免疫激活和旁观者凋亡的能力。了解TGF-21如何被转录调控的意义并不仅仅与HIV-1疾病相关。这种多效性免疫抑制和促凋亡细胞因子在其他感染性疾病、自身免疫和癌症（HTLV-I、多发性硬化症、胶质瘤等）中起关键作用。公共卫生相关性：免疫抑制是进行性HIV-1疾病的一个关键特征。在慢性HIV感染期间，抗病毒细胞介导反应的持续下调和免疫调节性t细胞的增加使免疫系统对病毒复制和机会性感染的控制失效。病毒蛋白HIV gp120和Tat已被归因于这种免疫抑制，但其潜在机制尚未明确定义。我们最近发现胶质瘤（Gli）转录因子在诱导Tbet蛋白中起重要作用，而Tbet蛋白在细胞介导的免疫应答中至关重要，并且HIV-1抑制Gli活性。本研究的目标是进一步阐明HIV-1调节人类Gli转录因子使t细胞从抗病毒Th1细胞向免疫抑制t细胞分化的机制。这些问题的答案无疑将导致对病毒发病机制和一般免疫学知识的增加。