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.
Human Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are capable of inducing tumor formation in immune-compromised individuals, including AIDS patients and organ transplant recipients. In immune-competent host, primary infection often results in life-long persistent infection. This study will develop a new strategy to block KSHV latent infection and boost T cell antiviral immunity via targeting a common denominator, an immune kinase.
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