microRNA Regulation of Gamma-herpesvirus Latency and Reactivation

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PROJECT SUMMARY Epstein-Barr virus (EBV) persistently infects >90% of adults worldwide. In individuals with congenital or acquired immune deficiencies, such as patients undergoing organ transplant or living with HIV/AIDS, life-long persistent infection can lead to a variety of cancers. Like all herpesviruses, EBV has both a latent and a lytic replication phase; the ability to switch between these programs is key to long-term viral persistence. Periodically, latent EBV reactivates to produce infectious virus, which is thought to increase the pool of infected cells and sustain persistent infection. Molecular mechanisms regulating latency and the switch to lytic replication are not entirely understood. MicroRNAs (miRNAs) are small, non-coding regulatory RNAs that govern many biological processes including cell state transitions and the development of immune responses. EBV encodes evolutionarily conserved viral miRNAs that are active during stages of the viral life cycle when viral proteins are highly restricted and that can interfere with host signaling pathways and anti-viral defense mechanisms on multiple levels, leading us postulate that viral miRNAs represent an important part of why host immune responses fail to clear persistent infection. Despite significant efforts advancing our understanding of EBV miRNA functions, little is known about their contributions to infection in vivo. Based on preliminary findings, we hypothesize that EBV miRNAs act as virulence factors and coordinate aspects of latency and reactivation that facilitate virus persistence within a host. In this project, we will examine regulatory non-coding RNA interactions, asking specifically how viral and cellular miRNAs cooperatively shape dynamic cell states during EBV infection, and determine the miRNAs influencing critical decisions that impact virus reactivation. We aim to elucidate the critical miRNAs and miRNA-mediated mechanisms (targets and pathways) regulating the EBV latent to lytic switch. To test our hypothesis that viral miRNAs facilitate persistence in vivo, we will leverage the rhesus lymphocryptovirus model to examine viral miRNA phenotypes in a natural primate host. Studies proposed herein have utility in developing RNA-based therapeutic strategies against viral disease and important implications for advancing g- herpesvirus vaccine development.