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.
|M Parrula, M Cecilia; Fernandez, Soledad A; Landes, Kristina et al. (2014) Success of measles virotherapy in ATL depends on type I interferon secretion and responsiveness. Virus Res 189:206-13|
|Dissinger, Nathan; Shkriabai, Nikoloz; Hess, Sonja et al. (2014) Identification and characterization of HTLV-1 HBZ post-translational modifications. PLoS One 9:e112762|
|Soodgupta, Deepti; Hurchla, Michelle A; Jiang, Majiong et al. (2013) Very late antigen-4 (*(4)*(1) Integrin) targeted PET imaging of multiple myeloma. PLoS One 8:e55841|
|Yang, Chang; Davis, Jennifer L; Zeng, Rong et al. (2013) Antagonism of inhibitor of apoptosis proteins increases bone metastasis via unexpected osteoclast activation. Cancer Discov 3:212-23|
|Kannian, Priya; Fernandez, Soledad; Jones, Kathryn S et al. (2013) Human T lymphotropic virus type 1 SU residue 195 plays a role in determining the preferential CD4+ T cell immortalization/transformation tropism. J Virol 87:9344-52|
|Hurchla, M A; Garcia-Gomez, A; Hornick, M C et al. (2013) The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Leukemia 27:430-40|
|Jacob, Aishwarya G; O'Brien, Dennis; Singh, Ravi K et al. (2013) Stress-induced isoforms of MDM2 and MDM4 correlate with high-grade disease and an altered splicing network in pediatric rhabdomyosarcoma. Neoplasia 15:1049-63|
|Sharma, Amit; Larue, Ross C; Plumb, Matthew R et al. (2013) BET proteins promote efficient murine leukemia virus integration at transcription start sites. Proc Natl Acad Sci U S A 110:12036-41|
|Kessl, Jacques J; Jena, Nivedita; Koh, Yasuhiro et al. (2012) Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem 287:16801-11|
|Heller, Emanuela; Hurchla, Michelle A; Xiang, Jingyu et al. (2012) Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Cancer Res 72:897-907|
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