Studies of p30 II and p13 II in HTLV-1 Infection

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DESCRIPTION (provided by applicant): This revised HIV-AIDS and Related Illnesses Research Collaboration (FIRCA) application proposes studies that will strengthen a collaboration between two highly productive research groups at The Ohio State University, USA (Drs. Lairmore and Green) and the University of Padova, Italy (Drs. Ciminale and D'Agostino). Critical to the continuation of these productive exchanges are funds to allow the collaborations to mature and to increase the research capacity of laboratories at the University of Padova. Human T-lymphotropic virus type 1 (HTLV-1) infection causes adult T-cell leukemia/lymphoma, occurs as a co-infection with HIV-1, and is associated with a variety of immune-mediated disorders. This complex retrovirus encodes typical gag, pol, and env gene products, as well as unique regulatory and accessory genes encoded in pX ORF I-IV. Critical roles of the viral accessory proteins in viral replication have recently emerged. Dr. Ciminale demonstrated that pl3" localizes to mitochondria, a property suggesting a unique role for this protein in the natural history of HTLV-1. Using molecular clones of HTLV-1 with selective mutations of pX ORFs I and 11, Dr. Lairmore's laboratory was the first to identify functional roles of p12', p13"/p301' for establishment of infection in the rabbit model and for infection of resting T-cells. In parallel, we now provide evidence that p30" functions as a transcription factor and differentially modulates CRE- and TRE-mediated transcription through CBP/p300. Together, our laboratories are in a unique position to test mechanisms by which these "accessory proteins" influence the replication and gene expression of HTLV-1. Specijc aims that will be addressed include: 1.Characterize the interaction of p30" with the coactivators, p300/CBP, and test the role of acetylation in p30"-mediated transcri tional activity, 2. Dissection of the targeting properties of p30" and analysis of the temporal expression of p30 and p13" mRNAs during virus replication, 3. Determine structural properties that regulate the subcellular localization and influence of HTLV-1 p13" on mitochondrial function. 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 US and foreign countries.