This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of this project is to identify the cellular and molecular mechanisms of Human Cytomegalovirus (HCMV) persistence in the host. Studies have implicated endothelial cells and macrophages as potential reservoirs of the virus in the host. We have shown that HCMV can persistently infect aortic endothelial cells (EC) in culture and have demonstrated HCMV sero-positive asymptomatic individuals harbor latent HCMV in peripheral blood myeloid cells. Furthermore, HCMV can be reactivated and isolated from allogeneically-stimulated monocyte derived macrophages (MDM). These studies have shown that MDM and EC play an important role in the biology and pathogenesis of HCMV. Understanding of HCMV replication and persistence in these cell types is limited, primarily due to inconsistent and restricted infection of MDM and EC by genetically characterized laboratory strains of HCMV. We have recently characterized a number of low passage clinical HCMV isolates for their growth in MDM and EC and have identified a strain (TR), which can consistently infect MDM as well as EC with high efficiency (100%). We hypothesize that HCMV encodes one or more genetic elements that enables the virus to infect and replicate in MDM and EC. Therefore, our goals in this project are to (1) identify the viral genes responsible for these viral phenotypes and (2) to characterize the mechanisms and products encoded by these genes using the proteomic technologies of the Resource that promote growth in MDM and EC. To address this objective, we will focus on the identification of the HCMV genes and gene products that determine growth in MDM and EC. Understanding the genetic basis of viral replication in MDM and EC will further our understanding of virus-host cell interactions that lead to viral persistence in the cell.
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