ENDOCYTIC TRAFFICKING OF ADENOVIRUS GENE THERAPY VECTORS

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DESCRIPTION: The future of gene therapy depends on our ability to find efficient means of delivering and expressing exogenous DNA. Strategies for gene transfer continue to progress along several lines including the use of viral vectors that capitalize on natural mechanisms of viral entry and establishment in eukaryotic cells. One of several viruses that provides a template for vector production is adenovirus (Ad), a virus that rides into cells by binding to cell surface proteins and entering cells as the plasma membrane is constitutively retrieved by a process called endocytosis. Once inside the cell, acidification of endosomes induces the virus to lyse the membrane that surrounds it and escape to the cytosol giving the virus access to the cell's nucleus. Escape from endosomes is crucial to viral survival. Dr. Leopold and his colleagues hypothesize that variation in the characteristics of endosomes from one cell type to another impacts the cell=s relative susceptibility to infection. They plan to investigate this possibility by (1) describing endocytosis of Ad in several distinct cell types that differ in susceptibility to Ad infection, (2) describing endocytosis of Ad during subtle manipulations of the endocytic process in a single cell type, and (3) describing endocytosis of variants of Ad vectors in a single cell type. From these studies, they expect to gain an understanding of the breadth of natural variation that exists in endocytic pathways as they affect Ad during infection, and to determine the key players at the molecular level that can influence the outcome of an Ad infection.