Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy

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.

[1]  V. Pascual,et al.  A genomic approach to human autoimmune diseases. , 2010, Annual review of immunology.

[2]  Y. Tabuchi,et al.  Distinct Roles of Transforming Growth Factor-β-activated Kinase 1 (TAK1)-c-Rel and Interferon Regulatory Factor 4 (IRF4) Pathways in Human T Cell Lymphotropic Virus 1-transformed T helper 17 Cells Producing Interleukin-9* , 2011, The Journal of Biological Chemistry.

[3]  Brian L. Pearlman,et al.  Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  J. Banchereau,et al.  Gene expression patterns in blood leukocytes discriminate patients with acute infections. , 2007, Blood.

[5]  Anne Wallace,et al.  IL-2- and STAT5-regulated cytokine gene expression in cells expressing the Tax protein of HTLV-1 , 2005, Oncogene.

[6]  S. Kinpara,et al.  Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon , 2009, Journal of Virology.

[7]  Virginia Pascual,et al.  An Interferon-Inducible Neutrophil-Driven Blood Transcriptional Signature in Human Tuberculosis , 2010, Nature.

[8]  C. Wijbrandts,et al.  Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients , 2007, Annals of the rheumatic diseases.

[9]  M. Kastan,et al.  Human T-Cell Leukemia Virus Type 1 Tax Attenuates the ATM-Mediated Cellular DNA Damage Response , 2008, Journal of Virology.

[10]  Aidan MacNamara,et al.  The Avidity and Lytic Efficiency of the CTL Response to HTLV-11 , 2009, The Journal of Immunology.

[11]  C L Verweij,et al.  A subtype of multiple sclerosis defined by an activated immune defense program , 2006, Genes and Immunity.

[12]  S. Izumo,et al.  Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: high proviral load strongly predisposes to HAM/TSP. , 1999, Journal of neurovirology.

[13]  M. Sitbon,et al.  HTLV-1 tropism and envelope receptor , 2005, Oncogene.

[14]  J. Zunt,et al.  Autoimmunity due to molecular mimicry as a cause of neurological disease , 2002, Nature Medicine.

[15]  B. Conrad.  Potential mechanisms of interferon-alpha induced autoimmunity. , 2003, Autoimmunity.

[16]  J. Weber,et al.  High frequencies of Th1-type CD4(+) T cells specific to HTLV-1 Env and Tax proteins in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. , 2002, Blood.

[17]  S. Goodbourn,et al.  Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. , 2008, The Journal of general virology.

[18]  S. Jacobson,et al.  Correlation of human T-cell lymphotropic virus type 1 (HTLV-1) mRNA with proviral DNA load, virus-specific CD8(+) T cells, and disease severity in HTLV-1-associated myelopathy (HAM/TSP). , 2002, Blood.

[19]  A. Lézin,et al.  HTLV-1 Evades Type I Interferon Antiviral Signaling by Inducing the Suppressor of Cytokine Signaling 1 (SOCS1) , 2010, PLoS pathogens.

[20]  M. Nagai,et al.  Human T-cell lymphotropic virus type I and neurological diseases , 2003, Journal of NeuroVirology.

[21]  F. Bushman,et al.  HTLV-1 Integration into Transcriptionally Active Genomic Regions Is Associated with Proviral Expression and with HAM/TSP , 2008, PLoS pathogens.

[22]  Joshua Arnold,et al.  Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1. , 2006, Blood.

[23]  T. Ohshima,et al.  HTLV-1 HBZ suppresses AP-1 activity by impairing both the DNA-binding ability and the stability of c-Jun protein , 2005, Oncogene.

[24]  G. Karypis,et al.  Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Dhib-jalbut,et al.  Interferon-β mechanisms of action in multiple sclerosis , 2010, Neurology.

[26]  V. Pascual,et al.  Systemic sclerosis and lupus: points in an interferon-mediated continuum. , 2010, Arthritis and rheumatism.

[27]  K. Jeang,et al.  Molecular mechanisms of cellular transformation by HTLV-1 Tax , 2005, Oncogene.

[28]  N. Tsuchida,et al.  Aberrant expression and function of p53 in T‐cells immortalized by HTLV‐I Tax1 , 1997, FEBS letters.

[29]  S. Hauser,et al.  The Neurobiology of Multiple Sclerosis: Genes, Inflammation, and Neurodegeneration , 2006, Neuron.

[30]  Y. Itoyama,et al.  CSF-chemokines in HTLV-I-associated myelopathy: CXCL10 up-regulation and therapeutic effect of interferon-α , 2005, Journal of Neuroimmunology.

[31]  M. Mochizuki,et al.  Human T lymphotropic virus type 1 uveitis. , 1994, The British journal of ophthalmology.

[32]  Yuetsu Tanaka,et al.  High frequency of CD4+FoxP3+ cells in HTLV-1 infection: inverse correlation with HTLV-1–specific CTL response , 2007, Blood.

[33]  B. Conrad.  Potential Mechanisms of Interferon-α Induced Autoimmunity , 2003 .

[34]  Yuetsu Tanaka,et al.  Monoclonal antibody defining tax protein of human T-cell leukemia virus type-I. , 1989, The Tohoku journal of experimental medicine.

[35]  M. Baba,et al.  Highly Enhanced Expression of CD70 on Human T-Lymphotropic Virus Type 1-Carrying T-Cell Lines and Adult T-Cell Leukemia Cells , 2008, Journal of Virology.

[36]  E. Majorovits,et al.  The immune control of HTLV-1 infection: selection forces and dynamics. , 2009, Frontiers in bioscience.

[37]  H. Zhi,et al.  Induction of p21CIP1/WAF1 expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization , 2009, Retrovirology.

[38]  A. Rosen,et al.  Type I interferons: crucial participants in disease amplification in autoimmunity , 2010, Nature Reviews Rheumatology.

[39]  J. M. Harris,et al.  Effect of pegylation on pharmaceuticals , 2003, Nature Reviews Drug Discovery.

[40]  L. Ratner,et al.  Human T-cell leukemia virus type 1 blunts signaling by interferon alpha. , 2008, Virology.

[41]  D. Meek.  Tumour suppression by p53: a role for the DNA damage response? , 2009, Nature Reviews Cancer.

[42]  S. Rahman,et al.  Murine FLT3 ligand-derived dendritic cell-mediated early immune responses are critical to controlling cell-free human T cell leukemia virus type 1 infection , 2014, Retrovirology.

[43]  F. Martin,et al.  Prospects for the management of human T-cell lymphotropic virus type 1-associated myelopathy. , 2011, AIDS reviews.

[44]  Sam Forster,et al.  INTERFEROME: the database of interferon regulated genes , 2008, Nucleic Acids Res..

[45]  P Rudge,et al.  In vivo cellular tropism of human T-cell leukemia virus type 1 , 1990, Journal of virology.

[46]  Virginia Pascual,et al.  A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. , 2008, Immunity.

[47]  Kousuke Saito,et al.  In vivo expression of the HBZ gene of HTLV-1 correlates with proviral load, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) , 2009, Retrovirology.

[48]  C. Bangham,et al.  The immune response to HTLV-I. , 2000, Current opinion in immunology.

[49]  Noula Shembade,et al.  Human T Cell Leukemia Virus Type 1 Tax Inhibits Innate Antiviral Signaling via NF-κB-Dependent Induction of SOCS1 , 2011, Journal of Virology.

[50]  Eshrat S. Emamian,et al.  Peripheral blood gene expression profiling in Sjögren’s syndrome , 2009, Genes and Immunity.

[51]  D. Wilkinson.  Gene Expression Patterns , 2002, Brain Research.

[52]  Y. Ohara,et al.  Infiltration of helper/inducer T lymphocytes heralds central nervous system damage in human T-cell leukemia virus infection. , 1992, The American journal of pathology.

[53]  P. Krammer,et al.  HTLV-1 Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory protein (c-FLIP). , 2006, Blood.

[54]  M. Piechaczyk,et al.  The HBZ Factor of Human T-cell Leukemia Virus Type I Dimerizes with Transcription Factors JunB and c-Jun and Modulates Their Transcriptional Activity* , 2003, Journal of Biological Chemistry.

[55]  Yuetsu Tanaka,et al.  Antigens related to three core proteins of HTLV‐I (p24, p19 and p15) and their intracellular localizations, as defined by monoclonal antibodies , 1986, International journal of cancer.

[56]  M. Boxus,et al.  The HTLV-1 Tax interactome , 2008, Retrovirology.

[57]  Kuan-Teh Jeang,et al.  Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation , 2007, Nature Reviews Cancer.

[58]  Y. Tabuchi,et al.  Human T Cell Lymphotropic Virus 1 Manipulates Interferon Regulatory Signals by Controlling the TAK1-IRF3 and IRF4 Pathways* , 2009, The Journal of Biological Chemistry.

[59]  Y. Itoyama,et al.  Natural killer (NK) cells in HTLV-I-associated myelopathy/tropical spastic paraparesis — decrease in NK cell subset populations and activity in HTLV-I seropositive individuals , 1991, Journal of Neuroimmunology.

[60]  J. Ho,et al.  Levels of serum chemokines discriminate clinical myelopathy associated with human T lymphotropic virus type 1 (HTLV‐1)/tropical spastic paraparesis (HAM/TSP) disease from HTLV‐1 carrier state , 2006, Clinical and experimental immunology.

[61]  D. Hedley,et al.  Whole blood fixation and permeabilization protocol with red blood cell lysis for flow cytometry of intracellular phosphorylated epitopes in leukocyte subpopulations , 2005, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[62]  Xu Wang,et al.  Interferon lambda inhibits herpes simplex virus type I infection of human astrocytes and neurons , 2011, Glia.

[63]  M. Nowak,et al.  HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[64]  M. Brown,et al.  The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis. , 2010, Human molecular genetics.

[65]  P. Rudge,et al.  Use of PCR to Investigate the Cellular Tropism of Human T Cell Leukemia Virus Type 1 , 1991 .