{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:46:28Z","timestamp":1760060788702,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human T-cell leukemia virus type 1 (HTLV-1) establishes lifelong infection and is associated with severe diseases such as adult T-cell leukemia\/lymphoma (ATL) and HTLV-1-associated myelopathy\/tropical spastic paraparesis (HAM\/TSP). Cytotoxic T lymphocytes (CTLs), especially those specific for the viral protein Tax, play a pivotal role in controlling HTLV-1 infection. However, conventional humanized mouse models fail to fully reconstitute human immune responses, limiting their utility for evaluating CTL-mediated immunity. This study aimed to establish a physiologically relevant in vivo model to investigate human CTL responses against HTLV-1. To achieve this, we utilized NOG-HLA-A02 transgenic (Tg) mice expressing human HLA-A02:01 on thymic epithelial cells, enabling proper development of HLA-restricted human T cells. Compared to conventional humanized NOG mice, HTLV-1-infected humanized NOG-HLA-A02 Tg mice exhibited significantly reduced HTLV-1 proviral load (PVL), decreased expansion of infected CD4+ T cells, a trend toward increased frequencies of Tax-specific CD8+ T cells, and prolonged survival. These results demonstrate that the expression of HLA-A02:01 facilitates robust CTL-mediated immune control of HTLV-1. This model provides a powerful platform for dissecting HTLV-1 immunopathogenesis and evaluating CTL-targeted therapeutic strategies, including vaccines and immune checkpoint inhibitors.<\/jats:p>","DOI":"10.3390\/v17091249","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T14:31:41Z","timestamp":1758033101000},"page":"1249","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An HTLV-1-Infected Humanized Mouse Model Expressing HLA-A*02:01 Demonstrates Effective CTL-Mediated Suppression of HTLV-1"],"prefix":"10.3390","volume":"17","author":[{"given":"Shinsuke","family":"Nakajima","sequence":"first","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Kansai Medical University, Hirakata 573-1010, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6288-4583","authenticated-orcid":false,"given":"Motohito","family":"Goto","sequence":"additional","affiliation":[{"name":"Central Institute for Experimental Medicine and Life Science (CIEM), Kawasaki 210-0821, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8330-1543","authenticated-orcid":false,"given":"Sung-Il","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Model Animal, Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tokifumi","family":"Odaka","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Kansai Medical University, Hirakata 573-1010, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Hino","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Kansai Medical University, Hirakata 573-1010, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenta","family":"Tezuka","sequence":"additional","affiliation":[{"name":"Center for Next Generation Biologics Research, National Institute of Infectious Diseases, Japan Institute for Health Security, Tokyo 208-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norihiro","family":"Takenouchi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Kansai Medical University, Hirakata 573-1010, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4746-2726","authenticated-orcid":false,"given":"Takaharu","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Kansai Medical University, Hirakata 573-1010, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fhahira Rizkhika","family":"Admadiani","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Kansai Medical University, Hirakata 573-1010, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1930-7075","authenticated-orcid":false,"given":"Riichi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Central Institute for Experimental Medicine and Life Science (CIEM), Kawasaki 210-0821, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isao","family":"Hamaguchi","sequence":"additional","affiliation":[{"name":"Center for Next Generation Biologics Research, National Institute of Infectious Diseases, Japan Institute for Health Security, Tokyo 208-0011, Japan"},{"name":"Department of Clinical Laboratory, Subaru Health Insurance Society Ota Memorial Hospital, Gunma 373-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Central Institute for Experimental Medicine and Life Science (CIEM), Kawasaki 210-0821, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5373-8223","authenticated-orcid":false,"given":"Mamoru","family":"Ito","sequence":"additional","affiliation":[{"name":"Central Institute for Experimental Medicine and Life Science (CIEM), Kawasaki 210-0821, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9719-0350","authenticated-orcid":false,"given":"Kazu","family":"Okuma","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine, Kansai Medical University, Hirakata 573-1010, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20160272","DOI":"10.1098\/rstb.2016.0272","article-title":"Human T-Cell Leukaemia Virus Type 1: Parasitism and Pathogenesis","volume":"372","author":"Bangham","year":"2017","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1182\/blood.V50.3.481.481","article-title":"Adult T-Cell Leukemia: Clinical and Hematologic Features of 16 Cases","volume":"50","author":"Uchiyama","year":"1977","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0140-6736(85)92734-5","article-title":"ANTIBODIES TO HUMAN T-LYMPHOTROPIC VIRUS TYPE-I IN PATIENTS WITH TROPICAL SPASTIC PARAPARESIS","volume":"326","author":"Gessain","year":"1985","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/S0140-6736(86)91298-5","article-title":"HTLV-I ASSOCIATED MYELOPATHY, A NEW CLINICAL ENTITY","volume":"327","author":"Osame","year":"1986","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1182\/blood-2009-12-257410","article-title":"Human T-Cell Leukemia Virus Type I (HTLV-1) Proviral Load and Disease Progression in Asymptomatic HTLV-1 Carriers: A Nationwide Prospective Study in Japan","volume":"116","author":"Iwanaga","year":"2010","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"586","DOI":"10.3109\/13550289809114225","article-title":"Analysis of HTLV-I Proviral Load in 202 HAM\/TSP Patients and 243 Asymptomatic HTLV-I Carriers: High Proviral Load Strongly Predisposes to HAM\/TSP","volume":"4","author":"Nagai","year":"1998","journal-title":"J. Neurovirol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Mohanty, S., and Harhaj, E.W. (2020). Mechanisms of Oncogenesis by HTLV-1 Tax. Pathogens, 9.","DOI":"10.3390\/pathogens9070543"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/348245a0","article-title":"Circulating CD8+ Cytotoxic T Lymphocytes Specific for HTLV-I PX in Patients with HTLV-I Associated Neurological Disease","volume":"348","author":"Jacobson","year":"1990","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1002\/jmv.20807","article-title":"Anti-HTLV-1 Tax Antibody and Tax-Specific Cytotoxic T Lymphocyte Are Associated with a Reduction in HTLV-1 Proviral Load in Asymptomatic Carriers","volume":"79","author":"Akimoto","year":"2007","journal-title":"J. Med. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5718","DOI":"10.4049\/jimmunol.177.8.5718","article-title":"Reduced Frequency, Diversity, and Function of Human T Cell Leukemia Virus Type 1-Specific CD8+ T Cell in Adult T Cell Leukemia Patients","volume":"177","author":"Kozako","year":"2006","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/1742-4690-8-100","article-title":"Functional Impairment of Tax-Specific but Not Cytomegalovirus-Specific CD8+ T Lymphocytes in a Minor Population of Asymptomatic Human T-Cell Leukemia Virus Type 1-Carriers","volume":"8","author":"Takamori","year":"2011","journal-title":"Retrovirology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1182\/blood.V97.4.987","article-title":"Existence of Escape Mutant in HTLV-I Tax during the Development of Adult T-Cell Leukemia","volume":"97","author":"Furukawa","year":"2001","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9389","DOI":"10.1128\/JVI.76.18.9389-9397.2002","article-title":"5\u2032-Long Terminal Repeat-Selective CpG Methylation of Latent Human T-Cell Leukemia Virus Type 1 Provirus In Vitro and In Vivo","volume":"76","author":"Koiwa","year":"2002","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/ijc.20007","article-title":"Genetic and Epigenetic Inactivation of TAX Gene in Adult T-Cell Leukemia Cells","volume":"109","author":"Takeda","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1093\/intimm\/dxh366","article-title":"Regulatory T Cell-like Activity of Foxp3+ Adult T Cell Leukemia Cells","volume":"18","author":"Chen","year":"2006","journal-title":"Int. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nakajima, S., and Okuma, K. (2023). Mouse Models for HTLV-1 Infection and Adult T Cell Leukemia. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202306.1746.v1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nri3311","article-title":"Humanized Mice for Immune System Investigation: Progress, Promise and Challenges","volume":"12","author":"Shultz","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mori, A., Murata, S., Tashiro, N., Tadokoro, T., Okamoto, S., Otsuka, R., Wada, H., Murata, T., Takahashi, T., and Seino, K.I. (2021). Establishment of Human Leukocyte Antigen-Mismatched Immune Responses after Transplantation of Human Liver Bud in Humanized Mouse Models. Cells, 10.","DOI":"10.3390\/cells10020476"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e7251","DOI":"10.1371\/journal.pone.0007251","article-title":"Dengue Virus Infection and Virus-Specific HLA-A2 Restricted Immune Responses in Humanized NOD-Scid IL2r\u03b3null Mice","volume":"4","author":"Jaiswal","year":"2009","journal-title":"PLoS ONE"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13022","DOI":"10.1073\/pnas.1000475107","article-title":"Generation of Functional Human T-Cell Subsets with HLA-Restricted Immune Responses in HLA Class I Expressing NOD\/SCID\/IL2r\u03b3null Humanized Mice","volume":"107","author":"Shultz","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","first-page":"3701","article-title":"Induction of APOBEC3B Cytidine Deaminase in HTLV-1-Infected Humanized Mice","volume":"17","author":"Yao","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e1010126","DOI":"10.1371\/journal.ppat.1010126","article-title":"M-Sec Induced by HTLV-1 Mediates an Efficient Viral Transmission","volume":"17","author":"Hiyoshi","year":"2021","journal-title":"PLoS Pathog."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.bbmt.2010.12.697","article-title":"Effects of Sublethal Irradiation on Patterns of Engraftment after Murine Bone Marrow Transplantation","volume":"17","author":"Andrade","year":"2011","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1538\/expanim.60.181","article-title":"Immunodeficient NOD-Scid IL-2R\u03b3null Mice Do Not Display T and B Cell Leakiness","volume":"60","author":"Katano","year":"2011","journal-title":"Exp. Anim."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1182\/blood-2013-06-508861","article-title":"An Animal Model of Adult T-Cell Leukemia: Humanized Mice with HTLV-1\u2013Specific Immunity","volume":"123","author":"Tezuka","year":"2014","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e1005560","DOI":"10.1371\/journal.ppat.1005560","article-title":"CADM1\/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis","volume":"12","author":"Manivannan","year":"2016","journal-title":"PLoS Pathog."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1158\/1078-0432.CCR-13-3169","article-title":"CADM1 Expression and Stepwise Downregulation of CD7 Are Closely Associated with Clonal Expansion of HTLV-I-Infected Cells in Adult T-Cell Leukemia\/Lymphoma","volume":"20","author":"Kobayashi","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12977-015-0236-7","article-title":"Rapid Dissemination of Human T-Lymphotropic Virus Type 1 during Primary Infection in Transplant Recipients","volume":"13","author":"Cook","year":"2016","journal-title":"Retrovirology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1182\/blood-2005-11-4388","article-title":"Reconstitution of a Functional Human Immune System in Immunodeficient Mice through Combined Human Fetal Thymus\/Liver and CD34+ Cell Transplantation","volume":"108","author":"Lan","year":"2006","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1038\/nm1431","article-title":"Humanized Mice Mount Specific Adaptive and Innate Immune Responses to EBV and TSST-1","volume":"12","author":"Melkus","year":"2006","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7305","DOI":"10.1128\/JVI.02207-08","article-title":"Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice","volume":"83","author":"Brainard","year":"2009","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1084\/jem.20081720","article-title":"Priming of Protective T Cell Responses against Virus-Induced Tumors in Mice with Human Immune System Components","volume":"206","author":"Strowig","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1182\/blood.V95.4.1386.004k22_1386_1392","article-title":"Abundant Tax Protein Expression in CD4+ T Cells Infected with Human T-Cell Lymphotropic Virus Type I (HTLV-I) Is Prevented by Cytotoxic T Lymphocytes","volume":"95","author":"Hanon","year":"2000","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"E1269","DOI":"10.1073\/pnas.1715724115","article-title":"Sporadic on\/off Switching of HTLV-1 Tax Expression Is Crucial to Maintain the Whole Population of Virus-Induced Leukemic Cells","volume":"115","author":"Mahgoub","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.4049\/jimmunol.1201518","article-title":"Characterization of Human Antiviral Adaptive Immune Responses during Hepatotropic Virus Infection in HLA-Transgenic Human Immune System Mice","volume":"191","author":"Billerbeck","year":"2013","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"28093","DOI":"10.1038\/srep28093","article-title":"Differential Effect of HLA Class-I versus Class-II Transgenes on Human T and B Cell Reconstitution and Function in NRG Mice","volume":"6","author":"Majji","year":"2016","journal-title":"Sci. Rep."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/9\/1249\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:34Z","timestamp":1760035594000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/9\/1249"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,16]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["v17091249"],"URL":"https:\/\/doi.org\/10.3390\/v17091249","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2025,9,16]]}}}