title: Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression.
abstract: BACKGROUND
  Immunogenetic evidence indicates that cytotoxic T lymphocytes (CTLs) specific for the weak CTL antigen HBZ limit HTLV-1 proviral load in vivo, whereas there is no clear relationship between the proviral load and the frequency of CTLs specific for the immunodominant antigen Tax. In vivo, circulating HTLV-1-infected cells express HBZ mRNA in contrast, Tax expression is typically low or undetectable. To elucidate the virus-suppressing potential of CTLs targeting HBZ, we compared the ability of HBZ- and Tax-specific CTLs to lyse naturally-infected cells, by co-incubating HBZ- and Tax-specific CTL clones with primary CD4(+) T cells from HLA-matched HTLV-1-infected donors. We quantified lysis of infected cells, and tested whether specific virus-induced host cell surface molecules determine the susceptibility of infected cells to CTL-mediated lysis.
  
  
  RESULTS
  Primary infected cells upregulated HLA-A*02, ICAM-1, Fas and TRAIL-R1/2 in concert with Tax expression, forming efficient targets for both HTLV-1-specific CTLs and CTLs specific for an unrelated virus. We detected expression of HBZ mRNA (spliced isoform) in both Tax-expressing and non-expressing infected cells, and the HBZ26-34 epitope was processed and presented by cells transfected with an HBZ expression plasmid. However, when coincubated with primary cells, a high-avidity HBZ-specific CTL clone killed significantly fewer infected cells than were killed by a Tax-specific CTL clone. Finally, incubation with Tax- or HBZ-specific CTLs resulted in a significant decrease in the frequency of cells expressing high levels of HLA-A*02.
  
  
  CONCLUSIONS
  HTLV-1 gene expression in primary CD4(+) T cells non-specifically increases susceptibility to CTL lysis. Despite the presence of HBZ spliced-isoform mRNA, HBZ epitope presentation by primary cells is significantly less efficient than that of Tax.
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, London, W2 1PG, UK. a.rowan@imperial.ac.uk.
authors.forename: Aileen G
authors.initials: AG
authors.lastname: Rowan
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, and Ehime University Proteomedicine Research Center, Toh-on city, Ehime, Japan. suemori@m.ehime-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Suemori
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, and Ehime University Proteomedicine Research Center, Toh-on city, Ehime, Japan. yunarief@m.ehime-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, and Ehime University Proteomedicine Research Center, Toh-on city, Ehime, Japan. yasukawa@m.ehime-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
authors.affiliation: Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. yuetsu@s4.dion.ne.jp.
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, London, W2 1PG, UK. g.p.taylor@imperial.ac.uk.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Taylor
authors.affiliation: Section of Virology, Department of Medicine, Imperial College London, London, W2 1PG, UK. c.bangham@ipmerial.ac.uk.
authors.forename: Charles R M
authors.initials: CR
authors.lastname: Bangham
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D003602:Cytotoxicity, Immunologic; D016356:Gene Products, tax / Q000276:immunology*; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D012191:Retroviridae Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D016356:Gene Products, tax; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; D014764:Viral Proteins; C514970:tax protein, Human T-lymphotrophic virus 1