SUMMARY Human cytomegalovirus (CMV) causes a spectrum of diseases in immunocompromised patients and serious birth defects when acquired during pregnancy. Limited therapeutic options have fostered efforts towards the development of effective vaccines and antibody therapeutics. Central to these endeavors has been a detailed molecular understanding of how CMV enters cells and overcomes intracellular antiviral mechanisms to replicate and spread. Although CMV transmission occurs orally, CMV tropism for oral mucosal epithelial, endothelial and Langerhans-type dendritic cells has not been studied. In addition, almost all CMV tropism studies conducted thus far have used viruses that have been passaged in cell culture. Our preliminary findings demonstrate that, in contrast to cell culture-derived viruses, CMV shed in urine enters and replicates in epithelial cells and LC with lower efficiencies compared to fibroblasts, showing that CMV, as it is exists in nature, differs dramatically from viruses grown in vitro. The proposed project seeks to address these important deficiencies through the following Aims: Aim I – Determine the tropisms of CMV, as it exists in urine and saliva, for oral epithelial, endothelial, and Langerhans-type dendritic cells. Aim II – Identify the antibodies that are most effective at restricting CMV entry and spread in oral mucosal cells. Aim III – Identify the viral genetic factors governing CMV tropisms for oral mucosal cells. These studies will provide a better understanding of the infectious properties of CMV, as shed in vivo, for cells directly involved in horizontal transmission, will provide data of critical importance for the design of vaccines and antibody therapies to protect against oral CMV transmission, and will reveal novel cell type- specific host restrictions and viral counter measures that could be exploited for intervention.