Viruses encode specific proteins that modify the regulatory machinery of the infected cell, overcoming host antiviral defenses and creating an optimal environment for viral replication. Mechanistic studies of virus-host interactions have provided a unique window into the workings of the cell and the origins of human cancer. We are interested in the ways in which herpesviruses modulate cellular transcription factors involved in control of cell proliferation; studies that will expand our understanding of the mammalian cell cycle and the virus-mediated oncogenesis.We have focused on two important viral regulatoy proteins: VP16 from herpes simplex virus (HSV) and LANA from Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8).

VP16, a potent transcriptional activator encoded by HSV, targets a conserved cellular factor known as HCF-1. Using a temperature-sensitive cell line, we have shown that HCF-1 is required for progression through G₁ phase of the cell cycle and acts as a coactivator for a variety of celluar transcription factors. To understand how HCF-1 promotes cell growth we are currently following two major directions: (i) the identification and analysis of other nuclear proteins that interact with HCF-1 or with HCF-2, a related protein identified in our lab and (ii) characterization of HCF function in the fruit fly Drosophila; an attractive model system that combines the power of genetics, biochemistry and developmental biology.

A second area under investigation in the lab is the role of KSHV in the development of Kaposi''''s sarcoma (KS), the leading tumor seen in AIDS patients and in the less common but more aggressive primary effusion lymphoma (PEL). We are interested in the establishment and maintenance of latent KSHV infection, focusing on the role of LANA in preventing p53-mediated apoptosis and in maintaining the viral genome during proliferation of the host cell. These studies will provide new insight into the mechanisms behind the immortalization of latently-infected B cells and endothelial cells - the first step towards development of KS or PEL tumors.