Insights gained through the study of retroviruses have established basic paradigms of cell biology, includingmechanisms of lymphocyte activation and proliferation. In Project 1 of P01 CA100730 we seek to continueto investigate fundamental questions of Human T-lymphotropic Virus Type 1 (HTLV-1), a complex retrovirusthat causes adult T-cell lymphoma/leukemia (ATL). HTLV-1 encodes typical gag, pol, and env geneproducts, and unique genes encoded in its pX region. In this highly collaborative PPG, we have pioneeredthe examination of the role of HTLV-1 proteins in viral replication in vivo and in lymphocyte activation, animportant antecedent to virus transmission and cell transformation. The focus of this project emerged fromthese studies and concentrates our proposed studies on p30 encoded in pX ORF II of HTLV-1. Thisnuclear/nucleolar protein has homology to transcription factors and contains G/SK consensus acetylationsites. 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, actsas 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 incell cycle perturbation and likely promote viral integration. Our data indicate that HTLV-1 uses p30 in a novelmanner 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 toidentify the roles of HTLV-1 p30 and HTLV-2 p28 (Project 2) by comparative testing of essentialtranscriptional and post-transcriptional control parameters. We have focused specific aims for thiscompetitive renewal of Project 1 on: 1) Localize important structural motifs of HTLV-1 p30 that mediatedtranscriptional regulation and DNA damage/repair signaling in T lymphocytes, 2) Determine the role of posttranslationmodifications in HTLV-1 p30 -mediated transcriptional regulation and DNA damage/repairsignaling in T lymphocytes, and 3) Test structural motifs important in p30 -mediated transcriptionalregulation and DNA damage/repair signaling in the spatial and temporal distribution of early virus expressionin rabbits with HTLV-1 molecular clones with selective mutations in pX ORF II. Our long-term goal is tounderstand how retroviruses, like HTLV-1 alter T cell physiology and thereby gain insight into mechanisms ofthe early phases of cell transformation and new targets of therapeutic intervention.
Showing the most recent 10 out of 162 publications
