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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE026003-03
Application #
9429100
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Chander, Preethi
Project Start
2016-04-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
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