The study of retroviruses have resulted in important discoveries and has lead to insights into basic cell biology including mechanisms of cell signaling, transcriptional and post transcriptional control of gene expression, and ultimately cellular transformation and cancer. Project 2 focuses on the human T-cell leukemia virus (HTLV) which is associated primarily with leukemia and highly valuable model of retrovirus induced cancer. The long-term objective of this highly interactive project is to understand virus-host interactions that regulate viral replication post-transcriptionally. We have shown that the post-transcriptional positive HTLV regulatory protein, Rex, the focus of the previous application, does not directly contribute to cellular transformation in vitro. We extended our work through collaboration to identify and characterize a novel function of HTLV-1 and HTLV-2 related accessory gene products that act post-transcriptionally as negative regulators of both Tax and Rex. Our exciting new function assigned to p28 and p30 as posttranscriptional control regulators provide the basis for the current proposal. We hypothesize that p28- mediated reduction of viral replication in T-lymphocytes and/or the proliferation of T-lymphocytes may permit survival of these cells by allowing escape from immune recognition, which would be consistent with the critical role of HTLV accessory proteins in viral persistence in vivo. We seek to define the post-transcriptional mechanisms of p28 repressive activity by 1) identifying and characterizing functional domains and biochemical properties of p28, 2) determining the primary sequence and structure/function of the p28 mRNA target, and 3) determining the contribution of p28 in viral replication, lymphocyte activation/transformation, and persistence of the virus and in vivo. Understanding the exact mechanism of action of post-transcriptional control of p28/p30 ultimately will provide a means for therapeutic targeting of these proteins to eradicate HTLV persistence in the host. Important to this PPG, our findings will contribute to understand how HTLV alters T-cell physiology and thus gain insight into the mechanisms of regulating viral replication and the early phases of lymphocyte activation and cellular transformation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S)
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Ohio State University
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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 αvβ3-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 β3 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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