title: Characterization of simian T-cell leukemia virus type 1 in naturally infected Japanese macaques as a model of HTLV-1 infection.
abstract: BACKGROUND
  Human T-cell leukemia virus type 1 (HTLV-1) causes chronic infection leading to development of adult T-cell leukemia (ATL) and inflammatory diseases. Non-human primates infected with simian T-cell leukemia virus type 1 (STLV-1) are considered to constitute a suitable animal model for HTLV-1 research. However, the function of the regulatory and accessory genes of STLV-1 has not been analyzed in detail. In this study, STLV-1 in naturally infected Japanese macaques was analyzed.
  
  
  RESULTS
  We identified spliced transcripts of STLV-1 corresponding to HTLV-1 tax and HTLV-1 bZIP factor (HBZ). STLV-1 Tax activated the NFAT, AP-1 and NF-κB signaling pathways, whereas STLV-1 bZIP factor (SBZ) suppressed them. Conversely, SBZ enhanced TGF-β signaling and induced Foxp3 expression. Furthermore, STLV-1 Tax activated the canonical Wnt pathway while SBZ suppressed it. STLV-1 Tax enhanced the viral promoter activity while SBZ suppressed its activation. Then we addressed the clonal proliferation of STLV-1⁺ cells by massively sequencing the provirus integration sites. Some clones proliferated distinctively in monkeys with higher STLV-1 proviral loads. Notably, one of the monkeys surveyed in this study developed T-cell lymphoma in the brain; STLV-1 provirus was integrated in the lymphoma cell genome. When anti-CCR4 antibody, mogamulizumab, was administered into STLV-1-infected monkeys, the proviral load decreased dramatically within 2 weeks. We observed that some abundant clones recovered after discontinuation of mogamulizumab administration.
  
  
  CONCLUSIONS
  STLV-1 Tax and SBZ have functions similar to those of their counterparts in HTLV-1. This study demonstrates that Japanese macaques naturally infected with STLV-1 resemble HTLV-1 carriers and are a suitable model for the investigation of persistent HTLV-1 infection and asymptomatic HTLV-1 carrier state. Using these animals, we verified that mogamulizumab, which is currently used as a drug for relapsed ATL, is also effective in reducing the proviral load in asymptomatic individuals.
authors.forename: Michi
authors.initials: M
authors.lastname: Miura
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Yasunaga
authors.forename: Junko
authors.initials: J
authors.lastname: Tanabe
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugata
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zhao
authors.forename: Guangyong
authors.initials: G
authors.lastname: Ma
authors.forename: Paola
authors.initials: P
authors.lastname: Miyazato
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kaneko
authors.forename: Akino
authors.initials: A
authors.lastname: Watanabe
authors.forename: Akatsuki
authors.initials: A
authors.lastname: Saito
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Akari
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Shogoin Kawahara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan. mmatsuok@virus.kyoto-u.ac.jp.
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000818:Animals; D006800:Deltaretrovirus Infections / Q000473:pathology / Q000662:veterinary* / Q000821:virology; D004195:Disease Models, Animal; D006801:Humans; D015458:Leukemia, T-Cell / Q000473:pathology / Q000662:veterinary* / Q000821:virology; D008251:Macaca; D018419:Primate Diseases / Q000473:pathology* / Q000821:virology*; D030261:Primate T-lymphotropic virus 1 / Q000254:growth & development / Q000302:isolation & purification* / Q000472:pathogenicity; D014412:Tumor Virus Infections / Q000473:pathology / Q000662:veterinary* / Q000821:virology