title: HTLV-1 evades type I interferon antiviral signaling by inducing the suppressor of cytokine signaling 1 (SOCS1).
abstract: Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of Adult T cell Leukemia (ATL) and the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1-infected individuals remain asymptomatic carriers (AC) during their lifetime, 2-5% will develop either ATL or HAM/TSP, but never both. To better understand the gene expression changes in HTLV-1-associated diseases, we examined the mRNA profiles of CD4+ T cells isolated from 7 ATL, 12 HAM/TSP, 11 AC and 8 non-infected controls. Using genomic approaches followed by bioinformatic analysis, we identified gene expression pattern characteristic of HTLV-1 infected individuals and particular disease states. Of particular interest, the suppressor of cytokine signaling 1--SOCS1--was upregulated in HAM/TSP and AC patients but not in ATL. Moreover, SOCS1 was positively correlated with the expression of HTLV-1 mRNA in HAM/TSP patient samples. In primary PBMCs transfected with a HTLV-1 proviral clone and in HTLV-1-transformed MT-2 cells, HTLV-1 replication correlated with induction of SOCS1 and inhibition of IFN-α/β and IFN-stimulated gene expression. Targeting SOCS1 with siRNA restored type I IFN production and reduced HTLV-1 replication in MT-2 cells. Conversely, exogenous expression of SOCS1 resulted in enhanced HTLV-1 mRNA synthesis. In addition to inhibiting signaling downstream of the IFN receptor, SOCS1 inhibited IFN-β production by targeting IRF3 for ubiquitination and proteasomal degradation. These observations identify a novel SOCS1 driven mechanism of evasion of the type I IFN antiviral response against HTLV-1.
authors.affiliation: Molecular Oncology Group, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Olière
authors.forename: Eduardo
authors.initials: E
authors.lastname: Hernandez
authors.forename: Agnès
authors.initials: A
authors.lastname: Lézin
authors.forename: Meztli
authors.initials: M
authors.lastname: Arguello
authors.forename: Renée
authors.initials: R
authors.lastname: Douville
authors.forename: Thi Lien-Anh
authors.initials: TL
authors.lastname: Nguyen
authors.forename: Stéphane
authors.initials: S
authors.lastname: Olindo
authors.forename: Gérard
authors.initials: G
authors.lastname: Panelatti
authors.forename: Mirdad
authors.initials: M
authors.lastname: Kazanji
authors.forename: Peter
authors.initials: P
authors.lastname: Wilkinson
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sékaly
authors.forename: Raymond
authors.initials: R
authors.lastname: Césaire
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015490:HTLV-I Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007370:Interferon Type I / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D015493:Paraparesis, Tropical Spastic / Q000235:genetics / Q000378:metabolism / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D014408:Biomarkers, Tumor; D007370:Interferon Type I; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012367:RNA, Viral; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins