Viral Genes Essential for MHV-68 Persistent Infection in the Spleen

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DESCRIPTION: Viral genes essential for MHV-68 Persistent Infection in the Spleen Members of the gammaherpesvirus subfamily are distinct in their ability to establish latent infections in the lymphocytes and cause benign or malignant tumors in infected hosts. There are two human viruses in this subfamily, Epstein-Barr virus (EBV) and human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV). Murine gammaherpesvirus-68 (MHV-68) is another member of the same subfamily. Since EBV and KSHV cannot effectively replicate in cell cultures or small model animals, MHV-68 serves as an excellent model system for studying the role of both the virus and the host in viral replication and pathogenesis. The function of viral genes can be determined in the MHV-68 system, which should provide instrumental information for the related genes in human gammaherpesviruses. The long-term goal of our discovery-oriented approach is to determine the function of each viral gene by mutagenesis of the whole viral genome. MHV-68 genome is mutagenized by random insertion of signature- tagged transposons into an MHV-68 bacterial artificial chromosome. The viral genes essential for viral replication in cell cultures have been identified. The objective of this exploratory R21 application is to identify viral genes essential for establishment of long-term persistent infection in the spleen. This study will be the first comprehensive analysis of viral gene function. The results will allow us to follow up on specific viral genes with hypothesis driven study. This will open a new window for us to look into the mechanism of viral persistence, which provides possibilities of identifying potential new therapeutic targets. Furthermore define the viral genes essential for persistent infection will allow us to construct recombinant viruses that are replication competent but cannot establish persistent infection. These viruses will strongly stimulate immune responses but will not establish persistent infection to cause diseases, thus a potential vaccine strategy.