Volume 12 Supplement 1

17th International Confernce on Human Retroviruses: HTLV and Related Viruses

Open Access

Role of protein arginine methyltransferase 5 over-expression in HTLV-1-driven cellular transformation and leukemia

  • Amanda R Panfil1, 2,
  • Jacob J Al-Saleem1, 2,
  • Jesse Kwiek1, 3,
  • Robert A Baiocchi5 and
  • Patrick L Green1, 2, 4, 5
Retrovirology201512(Suppl 1):P18

https://doi.org/10.1186/1742-4690-12-S1-P18

Published: 28 August 2015

Human T-cell leukemia virus-1 (HTLV-1) is a retrovirus that infects an estimated 15-25 million people worldwide. HTLV-1 is the causative infectious agent of adult T-cell leukemia/lymphoma (ATL) and a neurodegenerative disease (HAM/TSP). While the probability of presenting any symptoms related to HTLV-1 infection is relatively low (5-10% for the lifetime of an infected individual), the disease progression and prognosis of those infected individuals who develop ATL is fatal, with a median survival range of 8-10 months. Unfortunately, ATL is highly chemotherapy resistant and while many current therapies improve ATL patient survival, the patients consistently relapse. Therefore, a need exists to develop treatments that improve ATL outcome. We have recently identified PRMT5 (protein arginine methyltransferase 5) as a potential target to modulate HTLV-1 gene expression. We find that PRMT5 levels are elevated in T-cell leukemia/lymphoma cell lines compared to freshly isolated naïve T-cells. Likewise, PRMT5 levels are elevated in total PBMCs isolated from ATL patients. However, PRMT5 RNA levels do not correlate to PRMT5 protein levels, suggesting a possible post-transcriptional method of regulation. Furthermore, we also show that PRMT5 levels are elevated during T-cell transformation by using HTLV-1 short-term immortalization assays. Utilizing shRNA vectors, we demonstrate that knockdown of endogenous PRMT5 results in decreased cellular proliferation and increased HTLV-1 viral gene expression. In addition, we observe a decrease in cell proliferation and an increase in viral gene expression when HTLV-1-infected/-transformed cells are treated with a novel small molecule inhibitor of PRMT5 (PRMT5i). Conversely, PRMT5i does not induce re-activation from HIV-1 chronically infected cells. We previously reported a protein-protein interaction between the HTLV-1 accessory protein, p30, and PRMT5. We further show PRMT5 enhances the ability of p30 to inhibit viral gene expression. In conclusion, we find PRMT5 to be a negative regulator of HTLV-1 and a potential target in HTLV-1-mediated disease.

Authors’ Affiliations

(1)
Center for Retrovirus Research, Comprehensive Cancer Center and Solove Research Institute
(2)
Department of Veterinary Biosciences, Comprehensive Cancer Center and Solove Research Institute
(3)
Department of Microbial Infection and Immunity, Comprehensive Cancer Center and Solove Research Institute
(4)
Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center and Solove Research Institute
(5)
The Ohio State University

Copyright

© Panfil et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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