Role of IRFs in the Innate Response to HIV

IRF 在 HIV 固有反应中的作用

• 批准号: 6695995
• 负责人: Paula M Pitha-Rowe
• 金额: $ 24.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6695995
• 关键词: CD4 molecule; DNA binding protein; HIV infections; cell line; chromosome translocation; dendritic cells; flow cytometry; functional /structural genomics; genetic promoter element; genetic regulation; genetic transcription; human immunodeficiency virus 1; immunogenetics; immunoregulation; interferons; macrophage; monocyte; phosphorylation; polymerase chain reaction; posttranslational modifications; regulatory gene; virus genetics; virus replication

DESCRIPTION (provided by applicant): The focus of the proposed study is to determine the role of IRF transcription factors in the innate response to HIV-I infection. Over the past few years we have identified and characterized three novel IRFs: IRF-3, IRF-5 and IRF-7. We have shown that these factors serve as direct transducers of virus mediated signaling and play a critical role in the induction of Type I interferons (IFN) and several chemokines in infected cells. We and others have shown that in cells infected both with RNA and DNA viruses these factors that reside in the cytoplasm are phosphorylated and translocated to nucleus where they form part of the transcription complex assembled on the promoters of IFNA and IFNB genes. There is also growing evidence that different viruses target the activation and function of cellular IRF-3 and IRF-7 to overcome the innate immune response. Studies of the immune control of HIV-1 infection has focused on the role of adaptive cellular antiviral response, while much less is known about the role of innate immune mechanisms in the control of HIV-1 infection. To fill this gap, the aim of the proposed study is to analyze the role of lRFs in the HIV mediated innate responses. The study has three aims: Aim1. The role of IRF-3, IRF-5 and IRF-7 in HIV replication. Here we shall determine how the expression levels of IRFs and their constitutively active mutants modulate HIV-1 replication and infection. Aim 2. Postranslational activation of IRF by HlV-1 mediated signaling. In this study we shall examine whether HIV-1 stimulated signaling cascades induce phosphorylation of IRFs, their nuc]ear translocation and transcription activation. Aim 3. The role of Nef in expression/activation of IRF factors. We shall determine whether Nef stimulates expression of iRF-3, 5 or 7 and induces their phosphoryJation and nuclear translocation or whether it blocks the function of these IRFs. This study should provide some basic insight into the role of innate response in control of HIV-1 infection. A better understanding of the initial antiviral immunity is essential for understanding HIV-1 pathogenesis and may be instrumental for developing new antiviral therapies.

描述（由申请人提供）：拟议研究的重点是确定 IRF 转录因子在 HIV-1 感染先天反应中的作用。在过去的几年中，我们已经识别并表征了三种新型 IRF：IRF-3、IRF-5 和 IRF-7。我们已经证明，这些因子可作为病毒介导信号传导的直接转导器，并在受感染细胞中诱导 I 型干扰素 (IFN) 和几种趋化因子中发挥关键作用。我们和其他人已经证明，在感染 RNA 和 DNA 病毒的细胞中，这些驻留在细胞质中的因子被磷酸化并易位到细胞核，在那里它们形成组装在 IFNA 和 IFNB 基因启动子上的转录复合物的一部分。还有越来越多的证据表明，不同的病毒以细胞 IRF-3 和 IRF-7 的激活和功能为目标，以克服先天免疫反应。 HIV-1感染的免疫控制研究主要集中在适应性细胞抗病毒反应的作用，而对于先天免疫机制在控制HIV-1感染中的作用知之甚少。为了填补这一空白，本研究的目的是分析 lRF 在 HIV 介导的先天反应中的作用。该研究有三个目标： Aim1。 IRF-3、IRF-5 和 IRF-7 在 HIV 复制中的作用。在这里，我们将确定 IRF 及其组成型活性突变体的表达水平如何调节 HIV-1 复制和感染。目标 2. HIV-1 介导的信号传导对 IRF 的翻译后激活。在这项研究中，我们将检查HIV-1刺激的信号级联是否诱导IRF的磷酸化、它们的核易位和转录激活。目标 3. Nef 在 IRF 因子表达/激活中的作用。我们将确定 Nef 是否刺激 iRF-3、5 或 7 的表达并诱导它们的磷酸化和核易位，或者它是否阻断这些 IRF 的功能。这项研究应该为先天反应在控制 HIV-1 感染中的作用提供一些基本的见解。更好地了解最初的抗病毒免疫对于了解 HIV-1 发病机制至关重要，并且可能有助于开发新的抗病毒疗法。