Research Project
10271837
PROJECT SUMMARY/ABSTRACT Human cytomegalovirus (HCMV) is a prototypical beta-herpesvirus that infects a majority of the world?s population. Although most HCMV infections are asymptomatic in healthy individuals, the virus is the leading cause of congenital abnormalities following fetal infection and is a significant cause of morbidity and mortality during transplant. HCMV is a species-specific virus that establishes a lifelong infection, characterized by latency or persistence in CD34+ hematopoietic progenitor cells (HPCs). As with all herpesviruses, HCMV latently-infected cells are sequestered from the immune responses and are controlled by the infecting virus. HCMV infection of HPCs results in significant effects on cellular hematopoiesis through both direct and indirect mechanisms ultimately controlling key cellular pathways involved in stem cell maintenance, differentiation, and function. During latency, HCMV expresses a limited number of genes necessary for maintenance of the virus, however we still lack an understanding of how many of these gene products function. HCMV UL4, a member of the RL11 region, is expressed during latency in primary cells, yet its function is unknown. The goal of this project is to determine the role of UL4 in HCMV latency and reactivation. Our preliminary data indicates that UL4 is one of the few genes expressed during latency and that it is required for latency and/or reactivation. We propose to characterize the functional molecular characteristics of UL4 including when and how UL4 is expressed during the viral lifecycle and whether UL4 functions as a cellular ligand. In parallel we will determine how UL4 controls HCMV latency and reactivation in HPCs including its role in latency establishment, genome maintenance, cellular differentiation, and/or reactivation initiation. This project will provide a comprehensive analysis of one of the limited viral latency gene products and define how UL4 controls latency. Understanding the processes behind viral latency are key to eradicating HCMV and its related pathologies.
