The human T cell leukemia virus type I (HTLV-1) is an oncogenic retrovirus associated with the genesis of adult T cell leukemia-lymphoma (ATLL) and a neuroinflammatory disease termed HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The determinants of disease initiation and progression are largely unknown but the effectiveness of the host immune response appears to play a major role. Although the adaptive immune response to HTLV-1 and subsequent immune evasion strategies have been studied in detail, little is known about mechanisms used by HTLV-1 to counteract the innate arm of the immune response. Type I interferon (IFN-o/p) is critical to restrict viral replication and establish a potent antiviral state. The expression of type I IFNs are tightly regulated and are strongly induced by virus infection due to the activation of Toll-dependent and independent innate antiviral signaling pathways. The Toll- independent pathways utilize the RNA helicases RIG-I and MDA-5 to detect viral RNA in the cytoplasm. Together with Dr. Barber, we have found that Tax is a potent inhibitor of both Toll-dependent and independent innate antiviral pathways. Tax inhibits these pathways in part by interacting with RIPI, a death domain containing protein that Dr. Barber's lab has recently identified as an essential component of RIG-I- mediated signaling. In addition to its effects on disrupting pathways that regulate IFN production, it was also found that Tax inhibits IFN signaling by a unique nuclear mechanism downstream of STATI phosphorylation and DNA binding. Relevant to these findings, we also found that Tax interacts with STATI and S0CS1, important regulators of IFN signaling. Therefore, Tax is a unique viral oncoprotein that disrupts multiple innate antiviral signaling pathways to inhibit IFN production and signaling. We propose to further define the mechanisms by which Tax inhibits these important signaling pathways. We will pursue the following specific aims: (1) Regulation of innate signaling by HTLV-1 Tax and (2) mechanisms of HTLV-1 Tax-mediated inhibition of IFN signaling. Completion of the proposed studies will provide mechanistic insight into the disruption of antiviral signaling pathways by Tax and may lead to novel therapeutics for HTLV-1 associated diseases.

Public Health Relevance

HTLV-1 is the etiological agent of adult T cell leukemia-lymphoma (ATLL), an aggressive malignancy of CD4+ T lymphocytes. Although the adaptive immune response to HTLV-1 has been extensively studied, little is known regarding the interplay between HTLV-1 and innate antiviral immunity, specifically type I interferon (IFN) related pathways. The focus of the proposal is to determine the mechanisms used by the HTLV-I- encoded Tax oncoprotein to antagonize the RIG-l/MDA-5 antiviral pathway and IFN signaling.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA128115-05
Application #
8546185
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$188,594
Indirect Cost
$61,778
Name
University of Miami School of Medicine
Department
Type
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Bayraktar, Ulas Darda; Diaz, Luis A; Ashlock, Brittany et al. (2014) Zidovudine-based lytic-inducing chemotherapy for Epstein-Barr virus-related lymphomas. Leuk Lymphoma 55:786-94
Charoenthongtrakul, Soratree; Gao, Linlin; Parvatiyar, Kislay et al. (2013) RING finger protein 11 targets TBK1/IKKi kinases to inhibit antiviral signaling. PLoS One 8:e53717
Gao, Linlin; Harhaj, Edward William (2013) HSP90 protects the human T-cell leukemia virus type 1 (HTLV-1) tax oncoprotein from proteasomal degradation to support NF-*B activation and HTLV-1 replication. J Virol 87:13640-54
Lavorgna, Alfonso; Harhaj, Edward W (2013) Is there a role for ubiquitin or SUMO in human T-cell leukemia virus type 2 Tax-induced NF-*B activation? Future Virol 8:223-227
Shembade, Noula; Harhaj, Edward W (2012) Regulation of NF-?B signaling by the A20 deubiquitinase. Cell Mol Immunol 9:123-30
Harhaj, Edward W; Dixit, Vishva M (2012) Regulation of NF-*B by deubiquitinases. Immunol Rev 246:107-24
Lavorgna, Alfonso; Harhaj, Edward W (2012) EBV LMP1: New and shared pathways to NF-ýýB activation. Proc Natl Acad Sci U S A 109:2188-9
Ramos, Juan Carlos; Lossos, Izidore S (2011) Newly emerging therapies targeting viral-related lymphomas. Curr Oncol Rep 13:416-26
Charoenthongtrakul, Soratree; Zhou, Qinjie; Shembade, Noula et al. (2011) Human T cell leukemia virus type 1 Tax inhibits innate antiviral signaling via NF-kappaB-dependent induction of SOCS1. J Virol 85:6955-62
Harhaj, Edward W; Dixit, Vishva M (2011) Deubiquitinases in the regulation of NF-?B signaling. Cell Res 21:22-39

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