Grant: Operating Grant

Polyomaviruses (PVs) are the cause of several diseases in humans, especially in individuals that are immunocompromised, such as AIDS patients, or those taking immunosuppressive drugs, such as organ transplant patients. The JC virus (JCV) causes progressive multifocal leukoencephalopathy, a disease of the brain commonly seen in AIDS patients. BKV on the other hand is the cause of BK-induced nephropathy, a major source of kidney transplant failures. Two recently discovered PVs, MCV and TSV, have been associated, respectively, with Merkel cell carcinoma, a rare but aggressive form of skin cancer, and trichodysplasia spinulosa, a rare skin disease seen exclusively in immune-deficient patients. Few therapeutic options are available to treat PV-associated diseases as no specific antiviral drug targeting these viruses currently exists. We propose to study how polyomaviruses usurp the cells that they infect in order to replicate (i.e. make copies of) their viral DNA genome, with the ultimate goal of discovering specific aspects of the infection process that could be targeted for antiviral drug discovery. A single viral protein, termed the "large T antigen", is required from the virus to replicate its genome, the rest of the proteins participating in the replication process being from the infected cell. We will identify which proteins from infected cells are required for viral DNA replication, in particular those that can bind to the viral large T antigen or that can alter its activity. We will also try to identify peptides that interfere with the functions of large T antigen, as such peptides are ideal tools to validate these functions as candidate antiviral targets. The proposed studies will greatly enhance our understanding of polyomavirus DNA replication and provide a basis for the discovery of inhibitors of this viral process, an essential first step in the development of antiviral drugs to treat polyomavirus induced-diseases.