Modulation of tumorigenesis by viral exosomes

Project 1 Project Summary Abstract This is a renewal application of a long-standing P01 grant. Our central hypothesis is that Extracellular Vesicles(EVs) or “exosomes” reprogram the tumor microenvironment of Kaposi Sarcoma (KS) and that these processes also affect neighboring EBV infected cells in the lymph nodes. In Sub-Saharan Africa, where both KSHV and EBV are endemic, approximately 40% of KSHV shedders also shed EBV”. Hence, we expect that even asymptomatic persons will have viral derived EVs in their circulation. About 1011 /ml EVs circulate in human plasma, as compared to ~104 infectious KSHV particles during systemic KS. The endothelial lining of blood and lymphatic vessels are continuously exposed to systemically circulating EVs and these are the lineage of origin for KS. All KSHV-derived EVs carry all KSHV microRNAs. If only one in a million plasma EVs are derived from a latent or lytic KSHV-infected cell, more KSHV miRNAs are transferred by EVs than viral genomes by virions. New this funding period, we will probe the interaction of KSHV EVs on EBV pathogenesis, image single EV particles, and explore novel ways to repurpose natural EVs for targeted KS therapy.