The laboratory studies the cell biology of small DNA virus assembly with emphasis on:
  1. characterizing sites of viral assembly in the cell nucleus, and
  2. defining mitogenic signals resulting from the initial contact of the virus capsid with cell surface gangliosides.

In polyomavirus infected cells, virion assembly appears to take place at distinct "foci" within the nucleus termed PML-nuclear bodies. We are investigating the role of PML-NBs in polyomavirus assembly in mouse cells, and using cryo-EM to image these "virus factories." Virus assembly at these foci also appears to recruit cell DNA damage response proteins, which are essential for virus replication.

The polyomavirus capsid protein VP1 binds specific cell surface ganglioside molecules as a first step in infection. The engagement of these molecules results in a mitogenic signal that facilitates subsequent viral genomic replication. Each species of polyomavirus has a different ganglioside specificity, making VP1 an excellent reagent to study ganglioside signaling. These studies are enabled by the use of ganglioside-deficient cell lines that can be reconstituted with the ganglioside of choice.

In addition to basic cell biology of virus infection, the laboratory is also pursuing translational research concerning the development of new human papillomavirus (HPV) vaccines. Infection with "high-risk" human papillomaviruses is associated with the subsequent development of cervical cancer. However, current vaccines are costly and thus unavailable to women in resource-poor areas of the world. We have found that the subunits (capsomeres) of the virus capsid are equivalent to the entire capsid in generating protective immunity in model animal systems. Capsomeres can be purified after expression in bacteria, and thus potentially offer a low cost alternative to the current vaccines. Capsomeres are now being optimized for GMP production, and human trials will be pursued in collaboration with industrial partners under the auspices of an NCI SPORE grant in Cervical Cancer.