{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:33:45Z","timestamp":1767180825014,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011104","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T00:00:00Z","timestamp":1676332800000}}],"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19cm0106365h, 21cm0106386h"],"award-info":[{"award-number":["19cm0106365h, 21cm0106386h"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K07512"],"award-info":[{"award-number":["JP20K07512"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019727","name":"Japan Cancer Society","doi-asserted-by":"publisher","award":["Project Mirai Research Grants"],"award-info":[{"award-number":["Project Mirai Research Grants"]}],"id":[{"id":"10.13039\/100019727","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    A small proportion of human T-cell leukemia virus type-1 (HTLV-1)-infected individuals develop adult T-cell leukemia\/lymphoma, a chemotherapy-resistant lymphoproliferative disease with a poor prognosis. HTLV-1-specific cytotoxic T lymphocytes (CTLs), potential anti-tumor\/virus effectors, are impaired in adult T-cell leukemia\/lymphoma patients. Here, using Japanese monkeys naturally infected with simian T-cell leukemia\/T-lymphotropic virus type-1 (STLV-1) as a model, we demonstrate that short-term-cultured autologous peripheral blood mononuclear cells (PBMCs) can serve as a therapeutic vaccine to activate such CTLs. In a screening test, STLV-1-specific CTL activity was detectable in 8\/10 naturally STLV-1-infected monkeys. We conducted a vaccine study in the remaining two monkeys with impaired CTL responses. The short-term-cultured PBMCs of these monkeys spontaneously expressed viral antigens, in a similar way to PBMCs from human HTLV-1 carriers. The first monkey was subcutaneously inoculated with three-day-cultured and mitomycin C (MMC)-treated autologous PBMCs, and then boosted with MMC-treated autologous STLV-1-infected cell line cells. The second monkey was inoculated with autologous PBMC-vaccine alone twice. In addition, a third monkey that originally showed a weak STLV-1-specific CTL response was inoculated with similar autologous PBMC-vaccines. In all three vaccinated monkeys, marked activation of STLV-1-specific CTLs and a mild reduction in the STLV-1 proviral load were observed. Follow-up analyses on the two monkeys vaccinated with PBMCs alone indicated that STLV-1-specific CTL responses peaked at 3\u20134 months after vaccination, and then diminished but remained detectable for more than one year. The significant reduction in the proviral load and the control of viral expression were associated with CTL activation but also diminished 6 and 12 months after vaccination, respectively, suggesting the requirement for a booster. The vaccine-induced CTLs in these monkeys recognized epitopes in the STLV-1 Tax and\/or Envelope proteins, and efficiently killed autologous STLV-1-infected cells\n                    <jats:italic>in vitro<\/jats:italic>\n                    . These findings indicated that the autologous PBMC-based vaccine could induce functional STLV-1-specific CTLs\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011104","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T14:42:02Z","timestamp":1675348922000},"page":"e1011104","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Vaccination with short-term-cultured autologous PBMCs efficiently activated STLV-1-specific CTLs in naturally STLV-1-infected Japanese monkeys with impaired CTL responses"],"prefix":"10.1371","volume":"19","author":[{"given":"Atsuhiko","family":"Hasegawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megumi","family":"Murata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoka","family":"Fujikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuniko","family":"Katagiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiko","family":"Nagano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takao","family":"Masuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madoka","family":"Kuramitsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinsuke","family":"Nakajima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-ichi","family":"Fujisawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazu","family":"Okuma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Poonam","family":"Grover","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maureen","family":"Kidiga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Akari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3433-2658","authenticated-orcid":true,"given":"Mari","family":"Kannagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"issue":"3","key":"ppat.1011104.ref001","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":"T Uchiyama","year":"1977","journal-title":"Blood"},{"issue":"8452","key":"ppat.1011104.ref002","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":"2","author":"A Gessain","year":"1985","journal-title":"Lancet"},{"issue":"8488","key":"ppat.1011104.ref003","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":"1","author":"M Osame","year":"1986","journal-title":"Lancet"},{"issue":"3","key":"ppat.1011104.ref004","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1128\/jvi.64.3.1278-1282.1990","article-title":"Sequence variants of human T-cell lymphotropic virus type I from patients with tropical spastic paraparesis and adult T-cell leukemia do not distinguish neurological from leukemic isolates","volume":"64","author":"S Daenke","year":"1990","journal-title":"J Virol"},{"issue":"4","key":"ppat.1011104.ref005","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1002\/ijc.2910470403","article-title":"Sequence variations in LTR and env regions of HTLV-I do not discriminate between the virus from patients with HTLV-I-associated myelopathy and adult T-cell leukemia","volume":"47","author":"T Kinoshita","year":"1991","journal-title":"Int J Cancer"},{"issue":"6298","key":"ppat.1011104.ref006","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":"S Jacobson","year":"1990","journal-title":"Nature"},{"issue":"1","key":"ppat.1011104.ref007","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12977-019-0484-z","article-title":"Impact of host immunity on HTLV-1 pathogenesis: potential of Tax-targeted immunotherapy against ATL","volume":"16","author":"M Kannagi","year":"2019","journal-title":"Retrovirology"},{"issue":"20","key":"ppat.1011104.ref008","doi-asserted-by":"crossref","first-page":"9610","DOI":"10.1128\/JVI.74.20.9610-9616.2000","article-title":"Prevention of adult T-cell leukemia-like lymphoproliferative disease in rats by adoptively transferred T cells from a donor immunized with human T-cell leukemia virus type 1 Tax-coding DNA vaccine","volume":"74","author":"T Ohashi","year":"2000","journal-title":"J Virol"},{"issue":"23","key":"ppat.1011104.ref009","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1093\/jnci\/93.23.1775","article-title":"Regression of human T-cell leukemia virus type I (HTLV-I)-associated lymphomas in a rat model: peptide-induced T-cell immunity","volume":"93","author":"S Hanabuchi","year":"2001","journal-title":"J Natl Cancer Inst"},{"key":"ppat.1011104.ref010","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":"A Takamori","year":"2011","journal-title":"Retrovirology"},{"issue":"1","key":"ppat.1011104.ref011","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1600-065X.2011.01017.x","article-title":"Oral tolerance","volume":"241","author":"HL Weiner","year":"2011","journal-title":"Immunol Rev"},{"key":"ppat.1011104.ref012","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1146\/annurev-immunol-041015-055318","article-title":"CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer","volume":"37","author":"LM McLane","year":"2019","journal-title":"Annu Rev Immunol"},{"issue":"2","key":"ppat.1011104.ref013","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/ijc.2910430214","article-title":"Modelling the risk of adult T-cell leukemia\/lymphoma in persons infected with human T-lymphotropic virus type I","volume":"43","author":"EL Murphy","year":"1989","journal-title":"Int J Cancer"},{"issue":"4","key":"ppat.1011104.ref014","first-page":"302","article-title":"HTLV-I serostatus of mothers of patients with adult T-cell leukemia and HTLV-I-associated myelopathy\/tropical spastic paraparesis","volume":"1","author":"C Bartholomew","year":"1998","journal-title":"J Hum Virol"},{"issue":"6","key":"ppat.1011104.ref015","first-page":"474","article-title":"Mother-to-child transmission of human T-cell leukemia virus type-I","volume":"76","author":"S Hino","year":"1985","journal-title":"Jpn J Cancer 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Kozako","year":"2011","journal-title":"Hum Immunol"},{"issue":"8","key":"ppat.1011104.ref019","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1111\/cas.13654","article-title":"Human T-cell lymphotropic\/leukemia virus type 1 (HTLV-1) Tax-specific T-cell exhaustion in HTLV-1-infected individuals","volume":"109","author":"A Masaki","year":"2018","journal-title":"Cancer Sci"},{"issue":"3","key":"ppat.1011104.ref020","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1111\/bjh.13302","article-title":"Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia\/lymphoma in a pilot study","volume":"169","author":"Y Suehiro","year":"2015","journal-title":"Br J Haematol"},{"issue":"3","key":"ppat.1011104.ref021","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1111\/cas.13948","article-title":"Maintenance of long remission in adult T-cell leukemia by Tax-targeted vaccine: A hope for disease-preventive 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leukemia virus type-I (HTLV-I)-specific T-cell responses detected using three-divided glutathione-S-transferase (GST)-Tax fusion proteins","volume":"313","author":"K Kurihara","year":"2006","journal-title":"J Immunol Methods"},{"issue":"18","key":"ppat.1011104.ref025","doi-asserted-by":"crossref","first-page":"4855","DOI":"10.1182\/blood-2010-11-316463","article-title":"Kinetics and intracellular compartmentalization of HTLV-1 gene expression: nuclear retention of HBZ mRNAs","volume":"117","author":"F Rende","year":"2011","journal-title":"Blood"},{"issue":"3","key":"ppat.1011104.ref026","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1111\/cas.14800","article-title":"Short-term cultured autologous peripheral blood mononuclear cells as a potential immunogen to activate Tax-specific CTL response in adult T-cell leukemia patients","volume":"112","author":"M Ishizawa","year":"2021","journal-title":"Cancer Sci"},{"issue":"2","key":"ppat.1011104.ref027","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/0042-6822(86)90336-3","article-title":"Human T-cell leukemia virus type I is a member of the African subtype of simian viruses (STLV)","volume":"148","author":"T Watanabe","year":"1986","journal-title":"Virology"},{"issue":"1","key":"ppat.1011104.ref028","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1006\/viro.1994.1097","article-title":"Genetic analysis and molecular phylogeny of simian T-cell lymphotropic virus type I: evidence for independent virus evolution in Asia and Africa","volume":"199","author":"KJ Song","year":"1994","journal-title":"Virology"},{"issue":"6","key":"ppat.1011104.ref029","first-page":"848","article-title":"Detection of type C virus particles in Japanese monkeys seropositive to adult T-cell leukemia-associated antigens.","volume":"73","author":"I 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Nerrienet","year":"1998","journal-title":"AIDS Res Hum Retroviruses"},{"issue":"2","key":"ppat.1011104.ref033","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/ajp.20043","article-title":"Transmission of STLV in a closed colony of macaques","volume":"63","author":"SW Parrish","year":"2004","journal-title":"Am J Primatol"},{"issue":"1","key":"ppat.1011104.ref034","first-page":"105","article-title":"Transmission dynamics of simian T-lymphotropic virus type 1 (STLV1) in a baboon breeding colony: predominance of female-to-female transmission","volume":"57","author":"JM d\u2019Offay","year":"2007","journal-title":"Comp Med"},{"issue":"2","key":"ppat.1011104.ref035","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1089\/aid.2010.0082","article-title":"Short communication: epidemiological evidence that simian T-lymphotropic virus type 1 in Macaca fuscata has an alternative transmission route to maternal infection","volume":"27","author":"K Eguchi","year":"2011","journal-title":"AIDS Res Hum Retroviruses"},{"issue":"1","key":"ppat.1011104.ref036","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s12977-020-00525-1","article-title":"Frequent horizontal and mother-to-child transmission may contribute to high prevalence of STLV-1 infection in Japanese macaques","volume":"17","author":"M Murata","year":"2020","journal-title":"Retrovirology"},{"issue":"11","key":"ppat.1011104.ref037","doi-asserted-by":"crossref","first-page":"5280","DOI":"10.1128\/JVI.00281-16","article-title":"Cellular Immune Responses against Simian T-Lymphotropic Virus Type 1 Target Tax in Infected Baboons","volume":"90","author":"I Castro","year":"2016","journal-title":"J Virol"},{"key":"ppat.1011104.ref038","doi-asserted-by":"crossref","first-page":"27150","DOI":"10.1038\/srep27150","article-title":"Enhancement of anti-STLV-1\/HTLV-1 immune responses through multimodal effects of anti-CCR4 antibody","volume":"6","author":"K Sugata","year":"2016","journal-title":"Sci Rep"},{"issue":"2","key":"ppat.1011104.ref039","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/ijc.2910400219","article-title":"Serological survey and virus isolation of simian T-cell leukemia\/T-lymphotropic virus type I (STLV-I) in non-human primates in their native countries","volume":"40","author":"K Ishikawa","year":"1987","journal-title":"Int J Cancer"},{"key":"ppat.1011104.ref040","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/1742-4690-10-118","article-title":"Characterization of simian T-cell leukemia virus type 1 in naturally infected Japanese macaques as a model of HTLV-1 infection","volume":"10","author":"M Miura","year":"2013","journal-title":"Retrovirology"},{"issue":"2","key":"ppat.1011104.ref041","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/S0165-5728(99)00175-7","article-title":"HTLV-I specific IFN-gamma+ CD8+ lymphocytes correlate with the proviral load in peripheral blood 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Med"},{"issue":"12","key":"ppat.1011104.ref047","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1086\/420832","article-title":"Human T cell lymphotropic virus (HTLV) type-1-specific CD8+ T cells: frequency and immunodominance hierarchy","volume":"189","author":"PK Goon","year":"2004","journal-title":"J Infect Dis"},{"issue":"6","key":"ppat.1011104.ref048","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1080\/13550280490521104","article-title":"Human T-cell leukemia virus type I Tax induces the expression of dendritic cell markers associated with maturation and activation","volume":"10","author":"K Mostoller","year":"2004","journal-title":"J Neurovirol"},{"issue":"1","key":"ppat.1011104.ref049","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.virol.2006.12.020","article-title":"Deregulated expression of CD40 ligand in HTLV-I infection: distinct mechanisms of downregulation in HTLV-I-transformed cell lines and ATL patients","volume":"362","author":"NS Harhaj","year":"2007","journal-title":"Virology"},{"issue":"5","key":"ppat.1011104.ref050","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1189\/jlb.0309172","article-title":"Presentation of human T cell leukemia virus type 1 (HTLV-1) Tax protein by dendritic cells: the underlying mechanism of HTLV-1-associated neuroinflammatory disease","volume":"86","author":"SL Manuel","year":"2009","journal-title":"J Leukoc Biol"},{"issue":"3","key":"ppat.1011104.ref051","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/ijc.2910400320","article-title":"Protection of cynomolgus monkeys against infection by human T-cell leukemia virus type-I by immunization with viral env gene products produced in Escherichia coli","volume":"40","author":"H Nakamura","year":"1987","journal-title":"Int J Cancer"},{"key":"ppat.1011104.ref052","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1099\/0022-1317-78-1-147","article-title":"Long-term persistence of protective immunity in cynomolgus monkeys immunized with a recombinant vaccinia virus expressing the human T cell leukaemia virus type I envelope gene","volume":"78","author":"K Ibuki","year":"1997","journal-title":"J Gen Virol"},{"key":"ppat.1011104.ref053","first-page":"87","article-title":"Chimeric peptide vaccine composed of B- and T-cell epitopes of human T-cell leukemia virus type 1 induces humoral and cellular immune responses and reduces the proviral load in immunized squirrel monkeys (Saimiri sciureus)","author":"M Kazanji","year":"2006","journal-title":"The Journal of general virology"},{"issue":"13","key":"ppat.1011104.ref054","doi-asserted-by":"crossref","first-page":"5939","DOI":"10.1128\/JVI.75.13.5939-5948.2001","article-title":"Immunogenicity and protective efficacy of recombinant human T-cell leukemia\/lymphoma virus type 1 NYVAC and naked DNA vaccine candidates in squirrel monkeys (Saimiri sciureus)","volume":"75","author":"M Kazanji","year":"2001","journal-title":"Journal of virology"},{"issue":"1","key":"ppat.1011104.ref055","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/ijc.2910370107","article-title":"Antigens related to three core proteins of HTLV-I (p24, p19 and p15) and their intracellular localizations, as defined by monoclonal antibodies","volume":"37","author":"Y Tanaka","year":"1986","journal-title":"Int J Cancer"},{"issue":"11","key":"ppat.1011104.ref056","doi-asserted-by":"crossref","first-page":"e1006722","DOI":"10.1371\/journal.ppat.1006722","article-title":"Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo","volume":"13","author":"R Furuta","year":"2017","journal-title":"PLoS Pathog"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1011104","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T00:00:00Z","timestamp":1676332800000}}],"container-title":["PLOS 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