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 in a small percentage of infected individuals, and for comparative studies the related but non pathogenic HTLV-2. 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. Hbz is encoded from a functional promoter present in the antisense strand at the 3'terminus of the HTLV-1 proviral genome. We extended our work through collaborations with Dr. Ratner (Project 4) and Dr. Niewiesk (Core C) to show that HBZ reduces Tax-mediated viral transcription, promotes the proliferation of HTLV-1 infected cells by altering the transcriptional activity of multiple cellular factors, and is required for viral persistence and tumor cell organ infiltration in vivo. This exciting work provides the basis for this highly integrative continuation project designed to determine the role of Hbz in transformation and disease. Our overall hypothesis is that uncovering the mechanism of actions of Hbz and defining the interplay between Hbz and Tax will provide important insight into HTLV-1 cellular transformation and disease and ultimately will provide means for therapeutic targeting to erradicate HTLV-1 persistence in the host. This highly integrated competing renewal proposal as referenced by Project and Core collaborations below has two Specific Aims.
Specific Aim 1 will dissect the mechanisms of action of Hbz focusing on Hbz mRNA activities (Project 2, 4, and Core B), the functional role of HBZ post-translational modification (Project 2 and Core B), and effects on cellular protein interactions and pathways with emphasis on Jun, and NFkB and interferon (IRF-1, IRF-7) regulation (Projects 2, 3 and 4).
Specific Aim 2 will combine in vitro (transformation assays) and in vivo (transgenic and humanized mice) approaches (Project 2, 3, 4, and Core C) to determine the interplay between HBZ and Tax in the cellular transformation and tumor induction process.
Approximately 15-25 million people worldwide are infected with HTLV-1 with a small percentage developing adult T-cell leukemia. The cancer is aggressive and there is currently no effective treatment. This project focuses on a novel viral gene encoded by the antisense strand of the HTLV-1 genome, termed Hbz. Our studies will provide a significant advance in our basic knowledge of the role of Hbz in transformation and disease and will have significant implications for therapeutic targeting.
|Panfil, Amanda R; Dissinger, Nathan J; Howard, Cory M et al. (2016) Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis. J Virol 90:3760-72|
|Esser, Alison K; Schmieder, Anne H; Ross, Michael H et al. (2016) Dual-therapy with Î±vÎ²3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model. Nanomedicine 12:201-11|
|Su, Xinming; Esser, Alison K; Amend, Sarah R et al. (2016) Antagonizing Integrin Î²3 Increases Immunosuppression in Cancer. Cancer Res 76:3484-95|
|Kawatsuki, A; Yasunaga, J-I; Mitobe, Y et al. (2016) HTLV-1 bZIP factor protein targets the Rb/E2F-1 pathway to promote proliferation and apoptosis of primary CD4(+) T cells. Oncogene 35:4509-17|
|Murphy, Jane; Hall, William W; Ratner, Lee et al. (2016) Novel interactions between the HTLV antisense proteins HBZ and APH-2 and the NFAR protein family: Implications for the HTLV lifecycles. Virology 494:129-42|
|Niewiesk, Stefan (2016) Animals Models of Human T Cell Leukemia Virus Type I Leukemogenesis. ILAR J 57:3-11|
|Panfil, Amanda R; Martinez, Michael P; Ratner, Lee et al. (2016) Human T-cell leukemia virus-associated malignancy. Curr Opin Virol 20:40-46|
|Kroep, J R; Charehbili, A; Coleman, R E et al. (2016) Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials. Eur J Cancer 54:57-63|
|Haines, Robyn A; Urbiztondo, Rebeccah A; Haynes 2nd, Rashade A H et al. (2016) Characterization of New Zealand White Rabbit Gut-Associated Lymphoid Tissues and Use as Viral Oncology Animal Model. ILAR J 57:34-43|
|Ratner, L; Rauch, D; Abel, H et al. (2016) Dose-adjusted EPOCH chemotherapy with bortezomib and raltegravir for human T-cell leukemia virus-associated adult T-cell leukemia lymphoma. Blood Cancer J 6:e408|
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