Insights gained through the study of retroviruses have established basic paradigms of cell biology, including mechanisms of lymphocyte activation and proliferation. In Project 1 of P01 CA100730 we seek to continue to investigate fundamental questions of Human T-lymphotropic Virus Type 1 (HTLV-1), a complex retrovirus that causes adult T-cell lymphoma/leukemia (ATL). HTLV-1 encodes typical gag, pol, and env gene products, and unique genes encoded in its pX region. In this highly collaborative PPG, we have pioneered the examination of the role of HTLV-1 proteins in viral replication in vivo and in lymphocyte activation, an important antecedent to virus transmission and cell transformation. The focus of this project emerged from these studies and concentrates our proposed studies on p30 encoded in pX ORF II of HTLV-1. This nuclear/nucleolar protein has homology to transcription factors and contains G/SK consensus acetylation sites. Our collaborative studies with Drs. Green, Ratner, and Boris-Lawrie (Projects 2, 3, 5, Cores A, B, & C) of this PPG provided the first evidence that p30 is required by the virus to establish infection in animals, acts as a transcription factor, is positively influenced by acetylation and binds the KIX domain of the co-activator, p300. We now provide exciting new data that implicate p30 in DMA damage/repair signaling that results in cell cycle perturbation and likely promote viral integration. Our data indicate that HTLV-1 uses p30 in a novel manner to modulate the cellular environment to favor cell survival and balances the influence of viral transactivation (i.e., Tax) to allow viral persistence. In our next phase of this PPG, we provide interdependent approaches to identify the roles of HTLV-1 p30 and HTLV-2 p28 (Project 2) by comparative testing of essential transcriptional and post-transcriptional control parameters. We have focused specific aims for this competitive renewal of Project 1 on: 1) Localize important structural motifs of HTLV-1 p30 that mediated transcriptional regulation and DNA damage/repair signaling in T lymphocytes, 2) Determine the role of posttranslation modifications in HTLV-1 p30 -mediated transcriptional regulation and DNA damage/repair signaling in T lymphocytes, and 3) Test structural motifs important in p30 -mediated transcriptional regulation and DNA damage/repair signaling in the spatial and temporal distribution of early virus expression in rabbits with HTLV-1 molecular clones with selective mutations in pX ORF II. Our long-term goal is to understand how retroviruses, like HTLV-1 alter T cell physiology and thereby gain insight into mechanisms of the early phases of cell transformation and new targets of therapeutic intervention.
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