Biology of Adenovirus and Adeno-Associated Virus Vectors
Infection of a mammalian cell by a virus occurs through a well orchestrated sequence of virus host-cell interactions. For each virus, the process of infection represents a spectacular example of co-evolution; where the virus has evolved molecular pathways designed to parasitize the molecular machinery of the host cell and the host has evolved molecular mechanisms to detect and eliminate the invading pathogen.
Our laboratory studies the biology of two viruses, Adenovirus (Ad) and Adeno-Associated virus (AAV) and their interaction with a target cell. Both of these viruses are used as viral vectors for gene therapy.
The biology of virus entry into a target cell is an essential step in the virus life cycle. In the case of adenovirus, three viral capsid proteins, hexon, penton and fiber, are primarily responsible for delivery of the viral genome to the nucleus of the cell. The efficiency of virus entry mediated by these proteins makes adenovirus an efficient gene transfer vector. Although these interactions mediate efficient entry into the host cell, they also induce an anti-viral immune response. Our laboratory is interested in the molecular biology of Ad activation of the immune system. Using a murine model we are currently studying the involvement of Ad capsid proteins in activation of antigen presenting cells (macrophage and dendritic cells).
Our interest in AAV centers on its ability to integrate in a site-specific manner into human chromosome 19. We have recently discovered an AAV DNA sequence (the p5IEE) that is the sole cis DNA element necessary to mediate site-specific integration. The p5IEE is a multi-functional sequence; it is a regulatable promoter for the Rep protein and it serves as the target substrate DNA for integration through interactions with cellular transcription factors.
- Genetic Modification of Viral Capsid Proteins: Retargeting adenovirus vectors and altering the immune response to virus infection.
- Dendritic Cell Activation by Adenovirus Infection: Dissection of the Innate and Adaptive Immune response to infection by Adenovirus and Adenovirus vectors.
- Characterization of Rep/p5IEE Mediated Site-Specific Integration by AAV.