title: Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of human T-cell leukemia virus type 1.
abstract: OBJECTIVE
  The immunopathogenic mechanisms responsible for debilitating neurodegenerative and oncologic diseases associated with human T-cell leukemia virus type 1 (HTLV-1) are not fully understood. Quality of cytotoxic T lymphocytes (CTLs) is being increasingly associated with the outcome of persistent HTLV-1 infection. In this respect, a patient cohort (from HTLV-1 endemic region) consisting of seronegative controls (controls), asymptomatic carriers (ACs), and patients with adult T-cell leukemia (ATL) or HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was analyzed for CD8(+) T cells polyfunctionality in response to the viral antigen Tax.
  
  
  RESULTS
  Compared to ACs, ATL and HAM/TSP patients had lower frequency and polyfunctionality of CTLs in response to Tax suggesting dysfunction of CD8(+) T cells in these individuals. As an underlying mechanism, programmed death-1 (PD-1) receptor was found to be highly unregulated in Tax-responsive as well as total CD8(+) T cells from ATL and HAM/TSP but not from ACs and directly correlated with the lack of polyfunctionality in these individuals. Further, PD-1 expression showed a direct whereas MIP-1α expression had an indirect correlation with the proviral load providing new insights about the immunopathogenesis of HTLV-associated diseases. Additionally, we identified key cytokine signatures defining the immune activation status of clinical samples by the luminex assay.
  
  
  CONCLUSIONS
  Collectively, our findings suggest that reconstitution of fully functional CTLs, stimulation of MIP-1α expression, and/or blockade of the PD-1 pathway are potential approaches for immunotherapy / therapeutic vaccine against HTLV-mediated diseases.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, 19104, USA.
authors.forename: Sharrón L
authors.initials: SL
authors.lastname: Manuel
authors.forename: Mohit
authors.initials: M
authors.lastname: Sehgal
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.forename: George
authors.initials: G
authors.lastname: Makedonas
authors.forename: Zafar K
authors.initials: ZK
authors.lastname: Khan
authors.forename: Jay
authors.initials: J
authors.lastname: Gardner
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Pooja
authors.initials: P
authors.lastname: Jain
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D058070:Asymptomatic Diseases; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology*; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008875:Middle Aged; D015493:Paraparesis, Tropical Spastic / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D019562:Viral Load; D055815:Young Adult
chemical_list: D054405:Chemokine CCL3; D016207:Cytokines; D016356:Gene Products, tax; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C514970:tax protein, Human T-lymphotrophic virus 1