Inflammatory Mediators of Gammaherpesvirus Reactivation

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DESCRIPTION (provided by applicant): The human gammaherpesviruses are Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). Each human gammaherpesvirus is closely associated with a number of malignancies, particularly in immunosuppressed transplant recipients or individuals with immunosuppression due to concurrent infection with human immunodeficiency virus. Like other herpesviruses, the gammaherpesviruses are characterized by their ability to establish latency in host cells. Reactivation from latency and subsequent lytic viral replication is an essential component of the gammaherpesvirus life cycle, allowing the virus to spread to other cells within the host or to other susceptible hosts. Molecular mechanisms underlying the process of gammaherpesvirus reactivation are increasingly understood, but specific exogenous stimuli that trigger these molecular events are not yet well defined. Clinical and experimental evidence suggests that coinfection with a second pathogen may serve as a stimulus for reactivation in a host latently infected with a gammaherpesvirus. Using a mouse model of coinfection, this application will test the hypothesis that acute infection with a second pathogen is capable of inducing reactivation of latent murine gammaherpesvirus 68 (MHV-68). The specific aims are to 1) determine whether coinfection induces reactivation of latent MHV-68, and 2) define the roles of select chemokines and cytokines in reactivation of latent MHV-68. Relevance to Public Health: The experiments outlined in this application will expand our understanding of how gammaherpesviruses reactivate, awakening from an inactive state in a persistently infected person in order to create new copies of virus capable of infecting other cells within the same person or infecting other individuals. Information gained from these experiments will contribute significantly to our understanding of gammaherpesvirus biology and pathogenesis and potentially will impact on strategies designed to treat gammaherpesvirus-related disease.