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Retrovirology. 2018 Nov 6;15(1):72. doi: 10.1186/s12977-018-0454-x.

Distinct gene expression signatures induced by viral transactivators of different HTLV-1 subgroups that confer a different risk of HAM/TSP.

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Department of Microbiology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.
Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, Fukuoka, Japan.
Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
Department of Social Work, Faculty of Human and Social Studies, Nagasaki International University, 2825-7 Huis Ten Bosch Machi, Sasebo, Nagasaki, 859-3298, Japan.
Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Department of Hematology, Rheumatology and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Department of Microbiology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan.



Among human T cell leukemia virus type 1 (HTLV-1)-infected individuals, there is an association between HTLV-1 tax subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. To investigate the role of HTLV-1 subgroups in viral pathogenesis, we studied the functional difference in the subgroup-specific viral transcriptional regulators Tax and HBZ using microarray analysis, reporter gene assays, and evaluation of viral-host protein-protein interaction.


(1) Transcriptional changes in Jurkat Tet-On human T-cells that express each subgroup of Tax or HBZ protein under the control of an inducible promoter revealed different target gene profiles; (2) the number of differentially regulated genes induced by HBZ was 2-3 times higher than that induced by Tax; (3) Tax and HBZ induced the expression of different classes of non-coding RNAs (ncRNAs); (4) the chemokine CXCL10, which has been proposed as a prognostic biomarker for HAM/TSP, was more efficiently induced by subgroup-A Tax (Tax-A) than subgroup-B Tax (Tax-B), in vitro as well as in unmanipulated (ex vivo) PBMCs obtained from HAM/TSP patients; (5) reporter gene assays indicated that although transient Tax expression in an HTLV-1-negative human T-cell line activated the CXCL10 gene promoter through the NF-κB pathway, there was no difference in the ability of each subgroup of Tax to activate the CXCL10 promoter; however, (6) chromatin immunoprecipitation assays showed that the ternary complex containing Tax-A is more efficiently recruited onto the promoter region of CXCL10, which contains two NF-κB binding sites, than that containing Tax-B.


Our results indicate that different HTLV-1 subgroups are characterized by different patterns of host gene expression. Differential expression of pathogenesis-related genes by subgroup-specific Tax or HBZ may be associated with the onset of HAM/TSP.


HAM/TSP; HBZ; HTLV-1; Microarray; Tax; Virus subgroup

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