Structure-Function Analyses of HIV Rev and HTLV Rex

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DESCRIPTION (provided by applicant): The present HIV-AIDS and Related Illnesses Research Collaboration (FIRCA) application proposes studies that will strengthen a newly developed collaboration between two highly productive research groups at The Ohio State University, USA (Dr. Patrick Green) and the University of Padova, Italy (Dr. Donna D'Agostino). Joint research projects between the participating laboratories emerged following the principal investigators' participation in the "10th International Conference on Human Retrovirology: HTLV and Related Viruses held in Dublin, Ireland, June 25-29, 2001. During the meeting, joint projects were discussed as outlined in the following proposal. Critical to the continuation of these productive exchanges are funds to allow the collaborations to mature for the benefit of the United States investigator and to enable expansion of the research capacity of the laboratory at the University of Padova, Italy. The proposed research will combine the resources that are established in each institution to be used for the collective benefit of both participants. HIV and HTLV are complex retroviruses whose expression is controlled by the viral regulatory proteins Tat and Rev (HIV) and Tax and Rex (HTLV). Together, our research laboratories have performed basic studies to define the role of regulatory proteins of each virus and are in a unique position to determine how these analogous regulatory proteins influence gene expression and replication of these complex retroviruses. Dr. Green's research group has shown that Tax is essential for cellular transformation and has identified a novel phosphorylation domain of Rex-2 that regulates its function. Dr. D'Agostino has shown that, through altemative splicing, HTLV-2 may produce truncated forms of Rex-2 termed x-III proteins that act as repressors of full-length Rex-2. More recently, her group demonstrated the functional importance of a loop region in Rev that influences several properties of the protein that are essential to its function. Specific aims that will be addressed in our proposed collaborative research are: 1) to explore the role of phosphorylation in the activity of the x-III proteins and examine their effect on HTLV-2 replication; and 2) to investigate the control of Rev's conformation and function by protein kinase C-mediated phosphorylation at serine residues and by isomerization of prolines in the loop region. The combined facilities and expertise brought together by the proposed AIDS-related FIRCA are unique, productive, and fulfill the mission of the Fogarty International Center to support collaborative research between the United States and foreign countries.