Amanda Panfil
Assistant Professor
Contact
panfil.6@osu.edu 614-292-7449 Veterinary Medicine Academic Building1900 Coffey Road
Columbus, OH 43210
Map Link
Department
Veterinary Biosciences
Center For Retrovirus Research
Selected Awards and Honors
- PLoS Pathogen Outstanding Young Investigator, International Workshop on Retroviral Pathogenesis, 2017
- REACH for Commercialization - Inspiring Female Entrepreneurship at OSU and Beyond, 2016
Professional Training and experience
- Research Scientist, The Ohio State University
- Postdoctoral Fellow, The Ohio State University
- PhD, Cellular and Molecular Biology, University of Wisconsin
- BA, Microbiology, Ohio Wesleyan University
Research Interests
- Genetic and epigenetic regulation of Human T-cell leukemia virus type 1 (HTLV-1)
- Molecular and cellular mechanisms of HTLV-1 gene expression and transformation of host cells
- Retroviral oncogenesis
Research Summary
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus and the causative infectious agent of both HAM/TSP, a chronic inflammatory disease of the central nervous system, and ATL, an aggressive and fatal disease of CD4+ T-cells. HTLV-1-associated disease development occurs after an extensive clinical latency period upwards of several decades and lacks ideal therapeutic strategies. Not only is prognosis poor, but the molecular mechanism(s) behind disease development are not greatly understood. My lab utilizes molecular tools, coupled with both in vitro and in vivo models of infection and disease, to understand the cellular and viral players involved in genetic and epigenetic regulation of HTLV-1 gene expression and oncogenesis.
Project 1. Role of HTLV-1 Envelope in Transformation and Disease:
HTLV-2 is genetically and immunologically related to HTLV-1. However, unlike HTLV-1, HTLV-2 is generally not associated with disease. Comparative studies between these related viruses have been, and continue to be, extremely informative for identifying specific virus-host interactions associated with the pathogenic process.
Both HTLV-1 and HTLV-2 preferentially transform T-cells in vitro. HTLV-1 mainly transforms CD4+ T-cells, while HTLV-2 largely transforms CD8+ T-cells. Previous work mapped the genetic determinant for transformation tropism to the viral envelope protein (Env) and found transformation tropism is not solely conferred at the level of entry, but ensues during the cellular transformation process that occurs several weeks after infection. My lab utilizes comparative studies between Env-1 and Env-2 to identify and target the molecular mechanism(s) of HTLV-1 CD4+ T-cell transformation tropism using both in vitro and in vivo approaches.
Project 2. Role of PRMT5 in HTLV-1 Transformation and T-Cell Proliferation:
Modification of chromatin plays a central role in regulating various gene expression programs required during different stages of cell growth and development. One such chromatin modification is arginine methylation. PRMT5 is a type II PRMT enzyme that may act as either a transcriptional activator or repressor through symmetric dimethylation of arginine residues on histone proteins H4 (H4R3) and H3 (H3R8). During my postdoctoral training, I found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATL patient PBMCs. Interestingly, inhibition of PRMT5 by a novel small molecule inhibitor had selective toxicity in HTLV-1-transformed T-cells. Therefore, we hypothesize that PRMT5 could be an important epigenetic regulator of the HTLV-1 T-cell transformation process. We currently study how PRMT5 regulates HTLV-1-mediated T-cell transformation and pathogenesis.
Ongoing Collaborations:
Genome Editing to Prevent HTLV-1 Disease: Several studies have shown at least two viral genes, tax and hbz, are individually linked to cytokine activation, cell proliferation, and eventual oncogenic transformation. Tax is the major driver of viral transcription, transformation, and immune dysregulation, while HBZ supports proliferation and survival of HTLV-1-transformed cells in vivo and in vitro. HTLV-1 ATL tumor cells typically do not express tax, while hbz is always expressed in HTLV-1-infected cells, PBMCs of HTLV-1-infected individuals, and ATL tumor cells. Together, these two viral proteins are essential to the pathophysiology of both HAM/TSP and ATL. Our work will test the hypothesis that CRISPR/Cas9 genomic editing will be an effective method to disable the HTLV-1 provirus and its proliferative-inducing and tumorigenic effects on infected T-cells both in vitro, using cell culture-based assays, and in vivo, using a transplantation model in NOG mice. This work is part of a NIH-funded R21 Grant (Collaborators: Dr. Patrick Green & Dr. Kristine Yoder).
Contributions of HBZ to HTLV-1 Pathobiology: A mounting body of evidence suggests HBZ protein expression is critical throughout HTLV-1-mediated tumorigenesis. Tax is frequently silenced (by epigenetic modifications or deletion of the 5’ LTR) in ATL patients, presumably through CTL-mediated host immune-surveillance pressure. Therefore, HBZ-targeting strategies have strong potential for ATL and HAM/TSP therapeutics. Our group is focused on identification and characterization of HBZ cellular binding partners and their effects within T-cells. Insight of these roles will allow us to not only refine the role of HBZ in T-cell transformation and development of disease, but also explore HBZ cellular targets as potential marks for disease prevention and treatment. This project is one of two Aims from a NIH Program Project Grant (Collaborator: Dr. Patrick Green).
- Member, Center for Retrovirus Research, The Ohio State University
- Member, Infectious Diseases Institute, The Ohio State University
- Member, International Retrovirology Association
Publications
Selected Publications
- Xiang J, Rauch DA, Huey DD, Panfil AR, Cheng X, Esser AK, Su X, Harding JC, Xu Y, Fox GC, Fontana F, Kobayashi T, Su J, Sundaramoorthi H, Wong WH, Jia Y, Rosol TJ, Veis DJ, Green PL, Niewiesk S, Ratner L, Weilbaecher KN. HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia. JCI Insight. 2019 Oct 3;4(19). doi: 10.1172/jci.insight.128713. PubMed PMID: 31578308.
- Panfil AR, London JA, Green PL, Yoder KE. CRISPR/Cas9 Genome Editing to Disable the Latent HIV-1 Provirus. Front Microbiol. 2018;9:3107. doi: 10.3389/fmicb.2018.03107. eCollection 2018. Review. PubMed PMID: 30619186; PubMed Central PMCID: PMC6302043.
- Kodigepalli KM, Li M, Bonifati S, Panfil AR, Green PL, Liu SL, Wu L. SAMHD1 inhibits epithelial cell transformation in vitro and affects leukemia development in xenograft mice. Cell Cycle. 2018;17(23):2564-2576. doi: 10.1080/15384101.2018.1550955. Epub 2018 Dec 4. PubMed PMID: 30474474; PubMed Central PMCID: PMC6300106.
- Panfil AR, Al-Saleem J, Howard CM, Shkriabai N, Kvaratskhelia M, Green PL. Stability of the HTLV-1 Antisense-Derived Protein, HBZ, Is Regulated by the E3 Ubiquitin-Protein Ligase, UBR5. Front Microbiol. 2018;9:80. doi: 10.3389/fmicb.2018.00080. eCollection 2018. PubMed PMID: 29441057; PubMed Central PMCID: PMC5797633.
- Kenney AD, Dowdle JA, Bozzacco L, McMichael TM, St Gelais C, Panfil AR, Sun Y, Schlesinger LS, Anderson MZ, Green PL, López CB, Rosenberg BR, Wu L, Yount JS. Human Genetic Determinants of Viral Diseases. Annu Rev Genet. 2017 Nov 27;51:241-263. doi: 10.1146/annurev-genet-120116-023425. Epub 2017 Aug 30. Review. PubMed PMID: 28853921; PubMed Central PMCID: PMC6038703.
- Webb LM, Amici SA, Jablonski KA, Savardekar H, Panfil AR, Li L, Zhou W, Peine K, Karkhanis V, Bachelder EM, Ainslie KM, Green PL, Li C, Baiocchi RA, Guerau-de-Arellano M. PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis. J Immunol. 2017 Feb 15;198(4):1439-1451. doi: 10.4049/jimmunol.1601702. Epub 2017 Jan 13. PubMed PMID: 28087667; PubMed Central PMCID: PMC5292587.
- Panfil AR, Martinez MP, Ratner L, Green PL. Human T-cell leukemia virus-associated malignancy. Curr Opin Virol. 2016 Oct;20:40-46. doi: 10.1016/j.coviro.2016.08.009. Epub 2016 Aug 31. Review. PubMed PMID: 27591679; PubMed Central PMCID: PMC5102797.
- Panfil AR, Dissinger NJ, Howard CM, Murphy BM, Landes K, Fernandez SA, Green PL. Functional Comparison of HBZ and the Related APH-2 Protein Provides Insight into Human T-Cell Leukemia Virus Type 1 Pathogenesis. J Virol. 2016 Jan 27;90(7):3760-72. doi: 10.1128/JVI.03113-15. PubMed PMID: 26819304; PubMed Central PMCID: PMC4794683.
- Panfil AR, Al-Saleem J, Howard CM, Mates JM, Kwiek JJ, Baiocchi RA, Green PL. PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival. Viruses. 2015 Dec 30;8(1). doi: 10.3390/v8010007. PubMed PMID: 26729154; PubMed Central PMCID: PMC4728567.
- Panfil AR, Al-Saleem JJ, Green PL. Animal Models Utilized in HTLV-1 Research. Virology (Auckl). 2013;4:49-59. doi: 10.4137/VRT.S12140. eCollection 2013. Review. PubMed PMID: 25512694; PubMed Central PMCID: PMC4222344.
- Raver RM, Panfil AR, Hagemeier SR, Kenney SC. The B-cell-specific transcription factor and master regulator Pax5 promotes Epstein-Barr virus latency by negatively regulating the viral immediate early protein BZLF1. J Virol. 2013 Jul;87(14):8053-63. doi: 10.1128/JVI.00546-13. Epub 2013 May 15. PubMed PMID: 23678172; PubMed Central PMCID: PMC3700198.
- Wille CK, Nawandar DM, Panfil AR, Ko MM, Hagemeier SR, Kenney SC. Viral genome methylation differentially affects the ability of BZLF1 versus BRLF1 to activate Epstein-Barr virus lytic gene expression and viral replication. J Virol. 2013 Jan;87(2):935-50. doi: 10.1128/JVI.01790-12. Epub 2012 Nov 7. PubMed PMID: 23135711; PubMed Central PMCID: PMC3554042.
- Hoebe EK, Wille C, Hopmans ES, Robinson (Panfil) AR, Middeldorp JM, Kenney SC, Greijer AE. Epstein-Barr virus transcription activator R upregulates BARF1 expression by direct binding to its promoter, independent of methylation. J Virol. 2012 Oct;86(20):11322-32. doi: 10.1128/JVI.01161-12. Epub 2012 Aug 15. PubMed PMID: 22896599; PubMed Central PMCID: PMC3457140.
- Robinson (Panfil) AR, Kwek SS, Kenney SC. The B-cell specific transcription factor, Oct-2, promotes Epstein-Barr virus latency by inhibiting the viral immediate-early protein, BZLF1. PLoS Pathog. 2012 Feb;8(2):e1002516. doi: 10.1371/journal.ppat.1002516. Epub 2012 Feb 9. PubMed PMID: 22346751; PubMed Central PMCID: PMC3276558.
- Robinson (Panfil) AR, Kwek SS, Hagemeier SR, Wille CK, Kenney SC. Cellular transcription factor Oct-1 interacts with the Epstein-Barr virus BRLF1 protein to promote disruption of viral latency. J Virol. 2011 Sep;85(17):8940-53. doi: 10.1128/JVI.00569-11. Epub 2011 Jun 22. PubMed PMID: 21697476; PubMed Central PMCID: PMC3165789.
- Bristol JA, Robinson (Panfil) AR, Barlow EA, Kenney SC. The Epstein-Barr virus BZLF1 protein inhibits tumor necrosis factor receptor 1 expression through effects on cellular C/EBP proteins. J Virol. 2010 Dec;84(23):12362-74. doi: 10.1128/JVI.00712-10. Epub 2010 Sep 22. PubMed PMID: 20861254; PubMed Central PMCID: PMC2976414.
- Dickerson SJ, Xing Y, Robinson (Panfil) AR, Seaman WT, Gruffat H, Kenney SC. Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. PLoS Pathog. 2009 Mar;5(3):e1000356. doi: 10.1371/journal.ppat.1000356. Epub 2009 Mar 27. PubMed PMID: 19325883; PubMed Central PMCID: PMC2654727.