HTLV-1 subgroups associated with the risk of HAM/TSP are related to viral and host gene expression in peripheral blood mononuclear cells, independent of the transactivation functions of the viral factors
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Among human T cell leukemia virus type 1 (HTLV-1)-infected individuals, the risk of developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) across lifetime differs between ethnic groups. There is an association between HTLV-1 tax gene subgroups (subgroup-A or subgroup-B) and the risk of HAM/TSP in the Japanese population. In this study, we investigated the full-length proviral genome sequences of various HTLV-1-infected cell lines and patient samples. The functional differences in the viral transcriptional regulators Tax and HTLV-1 bZIP factor (HBZ) between each subgroup and the relationships between subgroups and the clinical and laboratory characteristics of HAM/TSP patients were evaluated. The results of these analyses indicated the following: (1) distinct nucleotide substitutions corresponding to each subgroup were associated with nucleotide substitutions in viral structural, regulatory, and accessory genes; (2) the HBZ messenger RNA (mRNA) expression in HTLV-1-infected cells was significantly higher in HAM/TSP patients with subgroup-B than in those with subgroup-A; (3) a positive correlation was observed between the expression of HBZ mRNA and its target Foxp3 mRNA in HAM/TSP patients with subgroup-B, but not in patients with subgroup-A; (4) no clear differences were noted in clinical and laboratory characteristics between HAM/TSP patients with subgroup-A and subgroup-B; and (5) no functional differences were observed in Tax and HBZ between each subgroup based on reporter gene assays. Our results indicate that although different HTLV-1 subgroups are characterized by different patterns of viral and host gene expression in HAM/TSP patients via independent mechanisms of direct transcriptional regulation, these differences do not significantly affect the clinical and laboratory characteristics of HAM/TSP patients.
KeywordsHTLV-1 Virus subgroup HAM/TSP Tax HBZ Foxp3
This work was supported by KAKENHI from the Japan Society for the Promotion of Science (JSPS) (Grant Numbers 21590512, 24590556, and 15K09345); the Health and Labor Sciences Research Grants (research on rare and intractable diseases, Grant Numbers H22-013, H23-126, H25-023, and H25-028); the Japan Agency for Medical Research and Development (AMED); the Project of Establishing Medical Research Base Networks Against Infectious Diseases in Okinawa; the Novartis Foundation for the Promotion of Science (Japan); and the Joint Usage/Research Center Program of the Institute for Virus Research, Kyoto University.
Compliance with ethical standards
The Institutional Review Boards of the authors’ institutions approved this research and written informed consent was obtained from all study participants.
Conflict of interest
The authors declare that they have no competing interests.
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