Peter Tattersall

Our research efforts are directed at understanding the molecular mechanisms by which mammalian parvoviruses target particular cell types, express their genes, take over their host cells and replicate their own DNA. Our major focus is on the genetic and biochemical analysis of the 83kd major non-structural protein NS1, a relatively stable nuclear phosphoprotein encoded by these viruses. This protein is intimately involved in viral transciptional regulation, DNA replication, and the negative control of host cell growth. Eukaryotic and prokaryotic expression systems, coupled with directed mutagenesis, are currently being used to separate the various functions of this complex, multi-functional protein, in order to understand how the virus subverts the macromolecular metabolism of its target host cell to its own ends. We are currently applying this knowledge to the construction of vectors for transducing genes antagonistic to HIV replication into human T-cells, as a therapeutic strategy against AIDS.

I wish to be contacted by interested students (medical, graduate or undergraduates) as a potential research mentor/thesis advisor.

How do the non-enveloped parvoviruses enter their host cell and get to the nucleus?
Enveloped viruses deliver their virions into the host cell by fusing their envelope with the cellular plasma or endosomal membrane, a strategy not available to non-enveloped viruses, which must employ alternative methods to breach their host cell's outer membrane. We have recently shown that the compact, icosahedral parvoviral virion gains entry to the cytoplasm from endosomes by deploying a lipolytic enzyme, phospholipase A2 (PLA2) that is expressed at the N-terminus of VP1, the minor coat protein. This region of VP1 is normally sequestered within the viral shell, but is extruded during the entry process as a capsid-tethered domain. The extruded VP1 N-terminus also displays a number of small protein interaction domains predicted to engage both ubiquitin ligases of the NEDD4 family, involved in endocytosis and vesicle trafficking, and nuclear transport proteins of the alpha-importin family. This project explores aspects of the trans-cytosolic trafficking and nuclear import of the murine parvovirus Minute Virus of Mice, MVM, using differential real-time PCR, directed genetics, sub-cellular fractionation and confocal microscopy.

Manipulating the oncoselectivity of parvoviruses in human tumor models.
Many of the rodent parvoviruses will initiate infection in human cells with high efficiency, but fail to generate progeny and spread through the culture unless the host cell is neoplastically transformed. This makes these viruses promising candidates as oncolytic agents. Our efforts are directed toward understanding the molecular basis of this phenomenon, and using such knowledge to improve the efficacy of the virus in tumor eridication. Since tumorigenesis normally involves loss of genomic integrity, most, if not all, tumor cells carry a myriad of mutations that are secondary to those causing the transformed phenotype. To avoid studying or selecting for viral traits that represent adaptations to such "collateral" transformed cell properties, we use as hosts cells that have been transformed in a stepwise fashion with defined oncogenes or tumor suppressor knock-downs. This project will examine the contribution of the viral initiating promoter to the discrimination between normal and transformed cells, and explore strategies for selecting more oncotropic versions of this critical transcriptional element.

Development of methods for the detection and elimination of parvoviral contaminants in industrial processes and products.
Development of parvoviral vectors for the treatment of cancer.
Development of parvoviral vectors for vaccination against infectious disease, including HIV-1 and Lyme Disease.