SUBVERSION OF HOST ANTIVIRAL DEFENSES BY HHV8 VIRF

HHV8 VIRF 颠覆宿主抗病毒防御

• 批准号: 6173889
• 负责人: MARGARET K OFFERMANN
• 金额: $ 26.92万
• 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/6173889
• 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（HHV 8）是一种最近发现的γ- 疱疹病毒，与疱疹病毒相关，最有可能的病原体 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与 HIV感染可能是这些疾病发病的重要因素 疾病，也许是通过改变宿主-病毒相互作用， 被感染的细胞 HHV 8基因组编码vIRF，这是一种基因产物， 与干扰素调节因子（IRF）家族转录同源 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 基因. 研究人员已经证明，vIRF抑制了对 I型和II型干扰素并阻断IRF-1介导的转录。 这表明vIRF与许多病毒蛋白质结合， 宿主抗病毒反应的靶向成分，并可进一步 损害已经受到以下损害的患者的免疫状态： 感染艾滋病毒。 此外，IRF-1是一种肿瘤抑制基因，而vIRF 可能有助于HHV 8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 vIRF改变干扰素应答并影响基因的机制 转录。 他们将检查特异性干扰素应答的敏感性， vIRF抑制基因。 他们已经证明， vIRF调控的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IRF位点结合，其响应于IRF 2而发生。 的 研究人员已经确定IRF-1的反式激活结构域是 他们建议完善他们对元素的分析， 受vIRF影响的IRF-1。 他们还将决定是否 vIRF中负责抑制IFN应答的元件 与抑制IRF-1介导的应答的那些相同或不同。 他们将识别和表征参与 vIRF介导的抑制反应。 他们将从年起继续学习 KS病变和原发性渗出性淋巴瘤细胞的体外系统， 在实验室中生成的试剂。 这些研究应该能提供 HHV 8编码的vIRF破坏宿主的作用机制 抗病毒反应，并有助于艾滋病毒的恶性转化 感染的病人。