SUBVERSION OF HOST ANTIVIRAL DEFENSES BY HHV8 VIRF

HHV8 VIRF 颠覆宿主抗病毒防御

• 批准号: 2717589
• 负责人: MARGARET K OFFERMANN
• 金额: $ 26.91万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/2717589
• 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

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型(HHV8)是最近发现的一种伽马病毒 与疱疹病毒有关的疱疹病毒，很可能是 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身上，这表明 免疫抑制、细胞因子失调或其他与 HIV感染可能是这些疾病发病的重要因素。 疾病，可能是通过改变宿主与病毒的潜伏相互作用 被感染的细胞。HHV8基因组编码vIRF，这是一种具有 与干扰素调节因子(IRF)转录家族同源 因子，一组相关的转录因子，调节表达 干扰素和其他抗病毒、免疫调节和生长调节 基因。研究人员已经证明，vIRF可以抑制对 I型和II型干扰素并阻断IRF-1介导的转录。 这表明vIRF结合了许多病毒蛋白，这些蛋白具有特异性 宿主抗病毒反应的靶成分，并可进一步 损害已经感染的患者的免疫状态 感染艾滋病毒。此外，IRF-1是一种肿瘤抑制基因，而vIRF 可能在HHV8感染细胞恶性转化中起作用 部分通过抑制IRF-1功能。调查人员将调查 VIRF改变干扰素反应和影响基因的机制(S) 抄写。他们将检查特定干扰素反应的敏感性。 基因对vIRF的抑制作用。他们已经证明了抑制基因的作用 IRF-1调节的转录不是竞争的结果 对于DNA结合，表明其机制不同于竞争 用于与响应IRF2而发生的IRF位点结合。这个 研究人员已经确定IRF-1的反式激活结构域是 以vIRF为目标，他们建议改进对元素的分析 在受vIRF影响的IRF-1内。他们还将决定是否 VIRF中负责抑制干扰素反应的元件 与抑制IRF-1介导的反应相同或不同。 他们将识别和表征参与 VIRF介导的抑制反应。他们将从印度扩展他们的研究范围。 KS病变和原发渗出性淋巴瘤细胞的体外系统 在他们的实验室里产生的试剂。这些研究应该会提供洞察力 HHV8编码的vIRF颠覆宿主的作用机制 抗病毒反应与HIV恶变的关系 被感染的病人。