Role of PVRL4 (Nectin-4) receptor in measles virus infections and oncolytic therapy

Our laboratory has been studying the cell receptors for measles virus for many years. Receptors are the molecules on the host cell to which the virus attaches, in order to initiate infection. Measles virus begins infection by attaching to one of the 3 receptors discovered by our laboratory (CD46/MCP, SLAM/CD150, PVRL4/Nectin-4). CD46 is only used by vaccine/laboratory adapted strains of measles virus, while wild type virus uses SLAM to enter lymphocytes and PVRL4 to infect epithelial cells. This proposal will study the entry and cell signaling events associated with PVRL4-virus interactions during the early stages of host cell infection. We will further assess the pathogenesis and spread of a measles/VSV hybrid virus in our mouse models that contain the human receptors. VSV is a cow virus which has recently been used as a vehicle to construct recombinant vaccines against pathogens such as HIV, rabies, and Ebola viruses. Finally, PVRL4 has previously been reported to be a tumor cell marker that is highly expressed on several cancer cell types. We have demonstrated that PVRL4 is found on many metastatic breast, prostate, bladder, ovarian, and pancreatic tumor cells. The oncolytic (tumor killing) properties of the measles/VSV hybrid virus will be assessed in mouse models that contain breast and ovarian tumors that express PVRL4. These studies are a prelude to oncolytic studies in dogs and humans using the PVRL4-targeting properties of measles and measles/VSV viruses. The approach could eventually be used to treat a wide variety of cancers known as adenocarcinomas.