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

描述(申请人提供)：全身性免疫激活和细胞凋亡是进行性HIV-1疾病的关键特征。HIV-1Tat蛋白与幼稚T细胞分化和凋亡的偏向有关，但其确切机制尚不清楚。GLI转录因子是重要的调节蛋白，参与细胞分化、增殖、凋亡和基因转录。我们已经在几个促炎症和促凋亡基因中发现了推测的GLI结合位点。我们的建议重点是Tbx21(Tbet)和转化生长因子-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，从而启动免疫特异性基因，从而诱导普遍的免疫激活和随后的细胞凋亡。此外，我们假设HIV-1Tat通过与转化生长因子-21启动子上的GLI2结合而诱导转化生长因子-21转录。这项建议的目的是进一步阐明HIV-1激活人类GLI转录因子以诱导负责免疫激活和细胞凋亡的基因转录的机制。具体地说，我们打算：1.阐明HIV-1调节Gli转录因子诱导Tbx21(Tbet)基因导致促炎Th1反应的机制。2.探讨HIV-1Tat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，从而使CD4+T细胞分化和/或凋亡发生倾斜。这些问题的答案无疑将增加对病毒发病机制和一般免疫学的了解。这些未知的途径也将是有价值的治疗靶点，以消除病毒诱导全身免疫激活和旁观者凋亡的能力。了解转化生长因子-21如何转录调控的意义并不完全与HIV-1疾病有关。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)中发挥关键作用。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，抗病毒细胞介导的反应持续下调，免疫调节T细胞增加，使免疫系统无法控制病毒复制和机会性感染。病毒蛋白HIV gp120和Tat被认为是这种免疫抑制的原因，但其潜在的机制尚未明确。我们最近发现，胶质瘤(Gli)转录因子在诱导Tbet蛋白的过程中起重要作用，而Tbet蛋白是细胞免疫反应中必不可少的，而HIV-1抑制Gli的活性。这项建议的目的是进一步阐明HIV-1调节人Gli转录因子以使T细胞分化从抗病毒Th1细胞转向免疫抑制T细胞的机制。这些问题的答案无疑将增加对病毒发病机制和一般免疫学的了解。

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.