Project 1: Role of HTLV-1 Hbz in Transformation and Disease

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PROJECT SUMMARY – PROJECT 1 The study of retroviruses has resulted in important discoveries and led to insights into basic cell biology including mechanisms of cell signaling, regulation of gene expression, and ultimately cellular transformation and cancer. Our collaborative work within this PPG focuses on HTLV-1, which is associated primarily with adult T-cell leukemia (ATL) and neurological disease (HAM/TSP) in a small percentage of infected individuals. Disease progression by HTLV-1 has been attributed to Tax, although we and others have hypothesized and provide data that another viral gene, termed Hbz, plays a critical role in the malignant process. Our presented data, as well as the work of others, indicate that hbz is multi-functional, playing important roles in both the RNA and protein form throughout infection and establishment of latency. We have extended our proposed work through PPG collaborations to better understand the manner in which hbz promotes proliferative and survival activity in cells. Proteomic analyses identified a panel of cellular proteins that distinctly interact with hbz RNA and HBZ protein. Functional characterization of these interactions are the next critical steps and the basis for this highly integrative continuation project designed to further define the role of hbz in transformation and disease. Our overall hypothesis is that uncovering the mechanism of actions of hbz RNA and HBZ protein will provide important insight into HTLV-1 cellular transformation and disease and ultimately will provide means for therapeutic targeting to eradicate HTLV-1 persistence in the host. This highly integrated proposal as referenced by Project and Core collaborations below has two Specific Aims. Aim 1 will dissect the mechanism(s) of action of hbz RNA and determine its contributions to the pathogenic process. We hypothesize that cellular protein interaction with hbz mRNA 2o structure translates to cell signaling pathways important for viral persistence and cellular proliferation. Our new proteomics data has identified, and we further validated, distinct cellular proteins that bind hbz mRNA. This aim will utilize in vitro approaches (Projects 2 and 3, Cores Admin/Biostats and Viral Vector) to identify the hbz RNA interactive region and determine the functional role of cellular binding proteins in cell proliferation. We will use in vivo approaches (Animal Core) to understand the contribution of the RNA and interactive proteins in the establishment of persistence and tumor formation. Aim 2 will dissect the mechanism(s) of action of HBZ protein and determine its contributions to HTLV-1 pathobiology. Our new proteomics data has identified, and we further validated, distinct cellular proteins that bind HBZ. In vitro approaches (Project 3, Cores Admin/Biostats and Viral Vector) including protein interaction mapping, cellular proliferation assays, and cellular transformation assays will be utilized to identify the HBZ interactive region and the functional role of key cellular binding proteins in HTLV-1 pathobiology. In vivo approaches (Animal Core, Project 2) will be used to determine the contribution of these HBZ interactive proteins in the establishment of persistence, infected cell survival, and tumor formation.