title: Truncated CXCL10 is associated with failure to achieve spontaneous clearance of acute hepatitis C infection.
abstract: The pathogenesis of hepatitis C virus (HCV) infection is strongly influenced by the nature of the host's antiviral immunity. Counterintuitively, elevated serum concentrations of C-X-C chemokine 10 (CXCL10), a potent chemoattractant for antiviral T-cells and NK-cells, are associated with poor treatment outcomes in patients with chronic HCV. It has been reported that an N-terminal truncated form of CXCL10, generated by the protease dipeptidylpeptidase 4 (DPP4), can act as chemokine antagonist. We sought to investigate CXCL10 antagonism in the clinical outcome and evolution of acute HCV infection. We collected serial blood samples from 16 patients, at the clinical onset of acute HCV infection and at 12 standardized follow-up timepoints over the first year. Intact and truncated CXCL10 and DPP4 activity were quantified in all longitudinal samples. In addition, NK-cell frequency/phenotype, and HCV-specific T-cell responses were assessed. Subjects developing chronicity (n = 11) had higher concentrations of CXCL10 (P < 0.001), which was predominantly in a truncated form (P = 0.036) compared to patients who spontaneously resolved infection (n = 5). Truncated CXCL10 correlated with HCV-RNA (r = 0.40, P < 0.001) and DPP4 activity (r = 0.53, P < 0.001). Subjects who resolved infection had a higher frequency of HCV-specific interferon-gamma (IFNγ)-producing T-cells (P = 0.017) and predominance of cytotoxic NK-cells (P = 0.005) compared to patients who became chronic. Patients who became persistently infected had higher proportions of cytokine-producing NK-cells, which were correlated with concentrations of truncated CXCL10 (r = 0.92, P < 0.001).
  
  
  CONCLUSIONS
  This study provides the first evidence of chemokine antagonism during acute HCV infection. We suggest that the DPP4-CXCL10 axis inhibits antiviral innate and adaptive host immunity and favors establishment of viral persistence.
authors.affiliation: Institute of Hepatology, Foundation for Liver Research, London, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Riva
authors.forename: Melissa
authors.initials: M
authors.lastname: Laird
authors.forename: Armanda
authors.initials: A
authors.lastname: Casrouge
authors.forename: Arvydas
authors.initials: A
authors.lastname: Ambrozaitis
authors.forename: Roger
authors.initials: R
authors.lastname: Williams
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Naoumov
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
authors.forename: Shilpa
authors.initials: S
authors.lastname: Chokshi
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000328:Adult; D054357:Chemokine CXCL10 / Q000097:blood / Q000276:immunology*; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D055815:Young Adult
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C508609:IL10 protein, human; D016753:Interleukin-10; D007371:Interferon-gamma; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4