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SUBVERSION OF HOST ANTIVIRAL DEFENSES BY HHV8 VIRF

HHV8 VIRF 颠覆宿主抗病毒防御

基本信息

批准号：
6513191
负责人：
MARGARET K OFFERMANN
金额：
$ 28.56万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-02 至 2003-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6513191
关键词：
Kaposi's sarcoma biological signal transduction clinical research gene expression human herpesvirus 8 human subject interferons lymphoma microorganism immunology polymerase chain reaction tissue /cell culture transcription factor virus protein virus related neoplasm /cancer

项目摘要

DESCRIPTION: Human herpes virus 8 (HHV8) is a recently identified gamma herpes virus that is associated with and most likely the etiologic agent of both Kaposi's sarcoma (KS) and primary effusion lymphomas. These conditions occur primarily in patients infected with HIV, suggesting that immunosuppression, cytokine dysregulation, or other factors associated with HIV infection may be important factors in the pathogenesis of these diseases, perhaps by altering the host-viral interaction in latently infected cells. The HHV8 genome encodes vIRF, a gene product that has homology to the interferon regulatory factor (IRF) family of transcription factors, a group of related transcription factors that regulate expression of interferon and other antiviral, immunomodulatory and growth regulatory genes. The investigators have demonstrated that vIRF inhibits responses to type I and type II interferons and blocks IRF-1-mediated transcription. This suggests that vIRF joins a number of viral proteins that specifically target components of the host antiviral responses and could further compromise the immunologic status of patients who are already compromised by infection with HIV. Furthermore, IRF-1 is a tumor suppressor gene, and vIRF may contribute to the malignant transformation of HHV8 infected cells in part by inhibiting IRF-1 function. The investigators will investigate the mechanism(s) by which vIRF alters interferon responses and affects gene transcription. They will examine the sensitivity of specific IFN-responsive genes to inhibition by vIRF. They have demonstrated that the inhibition of IRF-1-regulated transcription by vIRF is not a consequence of competition for DNA binding, indicating that the mechanism differs from the competition for binding to the IRF site that occurs in response to IRF2. The investigators have determined that the transactivation domain of IRF-1 is targeted by vIRF, and they propose to refine their analysis of elements within IRF-1 that are affected by vIRF. They will also determine whether the elements in vIRF that are responsible for inhibition of IFN responses are the same or distinct from those that inhibit IRF-1-mediated responses. They will identify and characterize proteins that are involved in vIRF-mediated inhibitory responses. They will extend their studies from in vitro systems to KS lesions and primary effusion lymphoma cells using reagents generated in their laboratory. These studies should offer insight into the mechanism of action by which HHV8-encoded vIRF subverts host antiviral responses and contributes to malignant transformation in HIV infected patients.

描述：人类疱疹病毒 8 (HHV8) 是最近发现的一种伽马病毒疱疹病毒与以下疾病有关，并且很可能是其病原体：卡波西肉瘤（KS）和原发性渗出性淋巴瘤。这些条件主要发生在感染艾滋病毒的患者中，这表明免疫抑制、细胞因子失调或其他相关因素 HIV感染可能是这些疾病发病机制的重要因素疾病，也许是通过改变潜伏的宿主与病毒的相互作用被感染的细胞。 HHV8 基因组编码 vIRF，这是一种基因产物，具有与干扰素调节因子 (IRF) 转录家族同源因子，一组调节表达的相关转录因子干扰素和其他抗病毒、免疫调节和生长调节药物基因。研究人员已经证明 vIRF 会抑制对 I 型和 II 型干扰素并阻断 IRF-1 介导的转录。这表明 vIRF 加入了许多病毒蛋白，这些蛋白专门靶向宿主抗病毒反应的成分，并可以进一步损害已经受到损害的患者的免疫状态感染艾滋病毒。此外，IRF-1是一种抑癌基因，而vIRF 可能有助于 HHV8 感染细胞的恶性转化部分通过抑制 IRF-1 功能。调查人员将调查此事 vIRF 改变干扰素反应并影响基因的机制转录。他们将检查特定干扰素反应的敏感性基因受 vIRF 抑制。他们已经证明，抑制 vIRF 调节的 IRF-1 转录不是竞争的结果对于 DNA 结合，表明该机制不同于竞争用于与响应 IRF2 发生的 IRF 位点结合。这研究人员确定 IRF-1 的反式激活结构域是 vIRF 的目标，他们建议完善元素分析受 vIRF 影响的 IRF-1 内。他们还将确定是否 vIRF 中负责抑制 IFN 反应的元件与抑制 IRF-1 介导的反应的那些相同或不同。他们将识别并表征参与的蛋白质 vIRF 介导的抑制反应。他们将从中扩展他们的学习使用体外系统对 KS 病变和原发性渗出性淋巴瘤细胞进行治疗在他们的实验室中产生的试剂。这些研究应该提供见解探究 HHV8 编码的 vIRF 颠覆宿主的作用机制抗病毒反应并有助于艾滋病毒的恶性转化感染的患者。