Targeting an immune kinase to purge KSHV latent infection

 描述(申请人提供)：人类疱疹病毒是最普遍的病原体，所有疱疹病毒的一个标志是能够在具有免疫能力的宿主中建立终身持续感染的能力。人类伽玛疱疹病毒，包括卡波西肉瘤相关疱疹病毒(KSHV)和EB病毒(EBV)，能够在免疫低下的人，包括艾滋病患者和器官移植受者中诱导肿瘤形成。事实上，发生艾滋病定义的恶性肿瘤，特别是卡波西氏肉瘤(KSHV)和非霍奇金淋巴瘤(EBV)的风险与免疫缺陷的程度高度相关。这些观察结果支持获得性免疫对控制KSHV和EBV持续感染至关重要的观点。因此，增强抗病毒免疫应能极大地降低与疱疹病毒感染相关的恶性肿瘤的可能性。我们最近发现，KSHV的新感染有效地激活了一种免疫激酶，以促进KSHV的潜伏感染。该激酶在T细胞中也高度表达，并作为T细胞激活的负调节因子发挥作用。在T细胞中，IMMUN激酶的激活与TCR结扎或钙内流诱导的T细胞激活相偶联。因此，我们建议剖析一种新的调控激酶激活的分子机制，并用小分子抑制剂灭活免疫激酶，以增强抗病毒T细胞免疫，清除持续的KSHV感染。我们的工作将建立一种新的策略，通过双重作用机制消除机会性病原体：灭活KSHV感染的内在前潜伏作用和激活外部T细胞抗病毒免疫。

 DESCRIPTION (provided by applicant): Human herpesviruses are the most ubiquitous pathogens and a hallmark of all herpesviruses is the ability to establish life-long persistent infection in an immune-competent host. Human gamma herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are capable of inducing tumor formation in immune-compromised individual, including AIDS patients and organ transplant recipients. In fact, the risk of developing AIDS-defining malignancies, especially Kaposi's sarcoma (KSHV) and non-Hodgkin's lymphoma (EBV), is highly associated with the level of immune-deficiency. These observations support the notion that adaptive immunity is crucial to control the persistent infection of KSHV and EBV. Consequently, boosting antiviral immunity should greatly minimize the potential to malignancies associated with herpesvirus infection. We have recently discovered that KSHV de novo infection potently activates an immune kinase to facilitate KSHV latent infection. The kinase is also highly expressed in T cells and functions as a negative regulator of T cell activation. In T cells, the activation of the immun kinase is coupled to T cell activation induced by TCR ligation or calcium influx. Thus, we propose to dissect a new molecular mechanism governing kinase activation and to inactivate the immune kinase with small-molecule inhibitors to boost antiviral T cell immunity and purge persistent KSHV infection. Our work will establish a new strategy to eliminate opportunistic pathogens via dual mechanisms of action: inactivating the intrinsic pro-latent role in KSHV infection and activating the extrinsic T cell antiviral immunity.