TREATMENT OF VIRUS ASSOCIATED PROLIFERATIVE DISORDERS

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Dr. Fingeroth is a clinician-scientist dedicated to patient-oriented research. The laboratory studies lymphotrophic herpesviruses (EBV and more recently HHV-8) that cause proliferative disorders in the compromised host and that are associated with several human tumors. Laboratory studies are organized to proceed from basic observations to translational research to the development of clinical protocols. Dr Fingeroth has mentored several young clinical and basic science investigators that have gone on to develop independent careers in patient-oriented research. She has support for her laboratory and excellent resources in the Division of Inf. Dis. at BWH/DFCI. The long-term goal of the proposed patient-oriented project is to develop an investigative group dedicated to identifying new mechanisms for eradicating virus infected human tumors based on the biology of the virus. This will be achieved through integrated studies directed by Dr. Fingeroth who will commit a minimum of 50 percent of her time to this effort. Although DNA tumor viruses encode gene products that are capable of destroying virus infected cells, these genes are silent during immortalizing/tumorigenic infection. Herpesviruses synthesize many proteins that support nucleic acid synthesis and protein processing functions required for efficient replication of viral DNA. The unique properties of viral enzymes has permitted development of antiviral drugs that can be converted to cytotoxic compounds with great specificity in virus infected cells. Some of these viral proteins form the basis of cytotoxic gene therapy (i.e. HSV TK and ganciclovir). The aims of this patient-oriented project are to identify gamma herpesvirus proteins, beginning with EBVTK and related early replicative products, that provide rational targets for cytotoxic anti-tumor therapy. This will be achieved by (1) by investigating the properties of gamma herpesvirus proteins predicted by homology to alpha/beta herpesviruses to function as targets for antiviral therapy - and documenting that they do so (2) by determining how the genes encoding these proteins are regulated in order to augment their expression in virus-infected tumors (3) by testing in vitro results in an animal model of EBV-associated lymphoproliferative disease and (4) by generating clinical protocols based on these findings to minimize the time between proof of concept and patient availability. Specific destruction of EBV infected lymphocytes by antiviral therapy could provide a significant new mechanism for eradicating EBV infected cells as in the case of B lymphoproliferative disease. The study is also likely to contribute significant knowledge in the basic understanding of EBV early gene regulation, and to identify other potentially cytotoxic effector proteins for treatment of virus infections, virus associated tumors and for gene therapy.