title: Systems biology approaches reveal a specific interferon-inducible signature in HTLV-1 associated myelopathy.
abstract: Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP.
authors.affiliation: Department of Immunology, Imperial College London, London, United Kingdom. sonja.tattermusch07@imperial.ac.uk
authors.forename: Sonja
authors.initials: S
authors.lastname: Tattermusch
authors.forename: Jason A
authors.initials: JA
authors.lastname: Skinner
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Jacques
authors.initials: J
authors.lastname: Banchereau
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Berry
authors.forename: Finlay W
authors.initials: FW
authors.lastname: McNab
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
authors.forename: Graham P
authors.initials: GP
authors.lastname: Taylor
authors.forename: Charles R M
authors.initials: CR
authors.lastname: Bangham
mesh_terms: D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D015683:Gene Products, gag / Q000378:metabolism; D016356:Gene Products, tax / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism* / Q000821:virology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D015493:Paraparesis, Tropical Spastic / Q000378:metabolism*; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D015683:Gene Products, gag; D016356:Gene Products, tax; D007370:Interferon Type I; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C514970:tax protein, Human T-lymphotrophic virus 1