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.

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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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZDE1-CF (10))
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Chander, Preethi
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University of Southern California
Schools of Medicine
Los Angeles
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Assadieskandar, Amir; Yu, Caiqun; Maisonneuve, Pierre et al. (2018) Effects of rigidity on the selectivity of protein kinase inhibitors. Eur J Med Chem 146:519-528
Liang, Qiming; Wei, Dahai; Chung, Brian et al. (2018) Novel Role of vBcl2 in the Virion Assembly of Kaposi's Sarcoma-Associated Herpesvirus. J Virol 92:
Zhang, Junjie; Zhao, Jun; Xu, Simin et al. (2018) Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication. Cell Host Microbe 24:234-248.e5
Chen, Ying-Chu; Backus, Keriann M; Merkulova, Maria et al. (2017) Covalent Modulators of the Vacuolar ATPase. J Am Chem Soc 139:639-642
Feldman, Emily R; Kara, Mehmet; Oko, Lauren M et al. (2016) A Gammaherpesvirus Noncoding RNA Is Essential for Hematogenous Dissemination and Establishment of Peripheral Latency. mSphere 1:
Zhu, Ying; Ramos da Silva, Suzane; He, Meilan et al. (2016) An Oncogenic Virus Promotes Cell Survival and Cellular Transformation by Suppressing Glycolysis. PLoS Pathog 12:e1005648
Zhang, Junjie; Feng, Hao; Xu, Simin et al. (2016) Hijacking GPCRs by viral pathogens and tumor. Biochem Pharmacol 114:69-81
Zhao, Jun; Zeng, Yi; Xu, Simin et al. (2016) A Viral Deamidase Targets the Helicase Domain of RIG-I to Block RNA-Induced Activation. Cell Host Microbe 20:770-784
Zhao, Jun; Li, Junhua; Xu, Simin et al. (2016) Emerging Roles of Protein Deamidation in Innate Immune Signaling. J Virol 90:4262-4268
Zhang, Junjie; Feng, Hao; Zhao, Jun et al. (2016) I?B Kinase ? Is an NFATc1 Kinase that Inhibits T Cell Immune Response. Cell Rep 16:405-418

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