ATM and gammaherpesvirus infection: a precarious balance

描述（由申请方提供）：γ疱疹病毒感染大多数人类，并与易感人群（包括HIV/AIDS患者）的癌症相关。更好地理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）激酶是一个重要的宿主因子，调节慢性γ疱疹病毒感染。我们假设T细胞的ATM表达是最佳γ疱疹病毒特异性适应性免疫应答的发展所必需的。与此同时，ATM在感染细胞中被篡夺，以促进病毒的重新激活。这些相反的功能建立了病毒-宿主平衡，当受到干扰时，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不足的人选择性地易受严重疱疹病毒感染。该假设将通过特定目的进行检验，预期这些目的为：1）确定ATM促进γ疱疹病毒再活化的分子机制; 2）确定ATM支持病毒特异性适应性免疫应答发展的机制; 3）确定ATM在长期感染期间对维持感染细胞库的贡献。成功完成拟议的研究将使我们能够更好地了解ATM对慢性γ疱疹病毒感染的调节，我们希望这一见解将刺激旨在控制高危人群（包括HIV患者）中γ疱疹病毒感染和发病机制的新治疗方法。

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.