Defining the proviral role of DnaJA1 in immune regulation and gammaherpesvirus infection

About This Grant

Project Summary Human gammaherpesviruses, Epstein Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), establish lifelong latent infection in >95% adults worldwide and are associated with several cancers, including B cell lymphomas. Poor control of viral infection, defined by elevated viral reactivation and latent viral load, precedes oncogenesis. However, due to the extreme species specificity of gammaherpesviruses, mechanisms underlying EBV and KSHV-driven lymphomagenesis remain poorly understood. To overcome this limitation, our lab utilizes murine gammaherpesvirus 68 (MHV68), a natural rodent pathogen sharing genetic, biologic, and pathogenic features of human gammaherpesviruses, including lymphomagenesis. The MHV68 experimental system allows us to study host mechanisms that control chronic viral infection in an intact host. Using the MHV68 model, my preliminary data establish that DnaJA1, a ubiquitously expressed host protein chaperone, supports viral DNA synthesis during lytic replication, viral reactivation, and establishment of latency. Importantly, we have uncovered that DnaJA1 is transcriptionally repressed by interferon regulatory factor-1 (IRF-1), which attenuates MHV68 lytic replication and establishment of latency. Thus, I hypothesize that suppression of DnaJA1 is one mechanism by which IRF-1 attenuates gammaherpesvirus infection. The proposed studies aim to determine mechanisms by which DnaJA1 supports viral DNA replication and attenuates the host immune response to support chronic viral infection. The proposed studies support a highly interdisciplinary training by taking advantage of virology, immunology, and molecular-based approaches to advance our understanding of host-virus interactions and immune control of chronic infection. Successful completion of the proposed aims has the potential to identify therapeutic targets to control chronic gammaherpesvirus infection and limit the development of virus-driven lymphomagenesis.