Project 4 Project Summary Abstract Kaposi sarcoma associated herpesvirus (KSHV) reprograms cells upon infection. This reprogramming of cell fate furthers lytic viral replication and latent genome persistence. One other outcome of this reprogramming is cellular transformation, such that KSHV-infected cells give rise to human cancer. KSHV reprograms endothelial cells to adopt a lymphatic phenotype, as opposed to a vascular phenotype. KSHV induces hyperplasia of these lymphatic endothelial cells. This eventually leads to complete transformation and the emergence of Kaposi sarcoma (KS). KSHV reprograms B cells, though it is unclear exactly which subset and what the direct outcome is. Eventually this, too, leads to complete transformation and the emergence of signature, KSHV-associated, B cell malignancies, i.e. a subclass of multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). We hypothesize that this reprogramming is mediated, at least in part, by viral microRNAs, some of which are secreted in the form of vesicles. We will investigate the function of the viral microRNAs either within the cell or circulating in blood (exosome) in culture and in mouse models.