ATM and gammaherpesvirus infection: a precarious balance

ATM 和伽玛疱疹病毒感染：不稳定的平衡

• 批准号: 9278127
• 负责人: Vera L. Tarakanova
• 金额: $ 31.75万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278127
• 关键词: AIDS/HIV problem; Adult; Affect; Antiviral Agents; Biochemical; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chromatin; Chronic; Clinical; Clinical Data; DNA Damage; Development; Equilibrium; Genetic Transcription; HIV; Herpesviridae Infections; Human; Immune response; Immunologics; Infection; Integration Host Factors; Knowledge; Lytic; Maintenance; Malignant Neoplasms; Molecular; Mus; Pathogenesis; Patients; Phosphotransferases; Population; Populations at Risk; Predisposition; Prevention; Publishing; Recruitment Activity; Regulation; Research; Response Latencies; Risk; Role; Switch Genes; T-Lymphocyte; Testing; Transgenic Organisms; Viral; Viral Pathogenesis; Virus; Virus Diseases; Virus Latency; adaptive immune response; ataxia telangiectasia mutated protein; cell type; design; experimental study; gammaherpesvirus; improved; in vivo; insight; mouse model; novel; novel strategies; novel therapeutic intervention; promoter; public health relevance; response; virus development

DESCRIPTION (provided by applicant): Gammaherpesviruses infect a majority of humans and are associated with cancer in susceptible populations, including HIV/AIDS patients. A better understanding of the mechanism whereby the host restricts chronic infection is likely to stimulate the development of new therapeutic approaches aimed at decreasing the risk of virus-driven cancer. Here we propose that Ataxia-Telangiectasia mutated (ATM) kinase is an important host factor that regulates chronic gammaherpesvirus infection. We hypothesize that ATM expression by T cells is required for the development of an optimal gammaherpesvirus-specific adaptive immune response. In parallel, ATM is usurped in infected cells to facilitate vira reactivation. These opposing functions establish a virus-host balance that, when perturbed, alters parameters of chronic infection and viral pathogenesis. This hypothesis is supported by our published and preliminary studies and clinical observations indicating that ATM insufficient humans are selectively susceptible to severe herpesvirus infection. The hypothesis will be tested by specific aims that are expected to 1) determine the molecular mechanism by which ATM facilitates gammaherpesvirus reactivation; 2) determine the mechanism by which ATM supports the development of virus-specific adaptive immune response, and 3) determine the contribution of ATM to the maintenance of infected cell reservoir during long-term infection. Successful completion of the proposed studies will allow a better insight into the regulation of chronic gammaherpesvirus infection by ATM, an insight that we hope will stimulate new therapeutic approaches aimed to control gammaherpesvirus infection and pathogenesis in at-risk populations, including HIV patients.

描述（由申请人提供）：伽玛疱疹病毒感染大多数人类，并与易感人群（包括艾滋病毒/艾滋病患者）的癌症相关。更好地了解宿主限制慢性感染的机制可能会刺激旨在降低病毒驱动的癌症风险的新治疗方法的开发。在这里，我们提出共济失调毛细血管扩张突变（ATM）激酶是调节慢性伽马疱疹病毒感染的重要宿主因子。我们假设 T 细胞表达 ATM 是产生最佳的伽马疱疹病毒特异性适应性免疫反应所必需的。与此同时，ATM 在受感染的细胞中被篡夺，以促进病毒重新激活。这些相反的功能建立了病毒-宿主平衡，当受到干扰时，会改变慢性感染和病毒发病机制的参数。这一假设得到了我们已发表的初步研究和临床观察的支持，表明 ATM 不足的人类选择性地容易受到严重疱疹病毒感染。该假设将通过具体目标进行检验，预计 1）确定 ATM 促进伽马疱疹病毒重新激活的分子机制； 2) 确定 ATM 支持病毒特异性适应性免疫反应发展的机制，以及 3) 确定 ATM 在长期感染期间对维持受感染细胞库的贡献。成功完成拟议的研究将有助于更好地了解 ATM 对慢性伽马疱疹病毒感染的调节，我们希望这一见解将激发新的治疗方法，旨在控制高危人群（包括艾滋病毒患者）的伽马疱疹病毒感染和发病机制。