Biology Of Cell-pathogen Interaction

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Abstract

Human T cell leukemia virus type I (HTLV-I) is an RNA tumor virus identified as a causative agent of adult T cell leukemia and shown to be associated with several neurological and chronic disorders. An estimated 10 to 20 million people are infected by HTLV-I. Of these only a small percentage develop symptomatic disease, the majority of infections are silent. The mechanisms of the development and pathogenesis of HTLV-I associated diseases remain unknown. Studies of human viral isolates as well as evidence from animal models yield no data to correlate disease with genetic variation in the virus. This project is focused on understanding the pathogenic mechanisms of HTLV-I by means of studies on the interaction between HTLV-I viral products and various cellular molecules. In vivo and in vitro studies utilize virus that is known to cause disease in rabbits compared to those that cause asymptomatic infection. Investigations focus on two distinct HTLV-I infected rabbit cell lines: RH/K30 which mediates asymptomatic infection and RH/K34, which causes acute leukemia-like diseases. Cell signaling mechanisms differ between the two lines and they differ in that one produces IL-10 whereas the other produces IL-4. IL-10 levels are increased in patients with T-cell leukemia suggesting a link to pathogenicity. Jak-STAT protein activation may be altered by treatment of the lines with cytokines and future studies will test whether switching of the activation pathway alters pathogenicity. In vivo studies indicate that HTLV-1 infected rabbits held for long period my develop cancer of epithelial cells and these harbor provirus. Work is progressing on the characterization of the cellular receptor for HTLV-1. A flow cytometric assay that measures the binding of intact HTLV-1 virions to the cell surface has been developed and is used to screen for compounds affecting viral binding. The assay is also being used to determine conditions influencing viral binding to the cell, such as temperature and divalent cation dependence.