title: Dynamic Changes of Post-Translationally Modified Forms of CXCL10 and Soluble DPP4 in HCV Subjects Receiving Interferon-Free Therapy.
abstract: Serum levels of the interferon (IFN)-stimulated chemokine CXCL10 are increased during chronic HCV infection and associate with outcome of IFN-based therapy. Elevated levels of NH2-terminal truncated CXCL10 (3-77aa), produced by DPP4 cleavage, negatively associate with spontaneous clearance of acute HCV infection and sustained virological response (SVR) with IFN-based therapy for chronic infection. The association of different CXCL10 forms and DPP4 with outcome during IFN-free HCV therapy has not been examined. Using novel Simoa assays, plasma was analyzed from HCV genotype-1 (GT1) subjects who relapsed (n = 11) or achieved SVR (n = 10) after sofosbuvir and ribavirin (SOF/RBV) treatment, and from SOF/RBV relapsers who achieved SVR with a subsequent SOF/ledipasvir regimen (n = 9). While the NH2-truncated form of CXCL10 was elevated in HCV infection relative to healthy controls, pre-treatment plasma concentrations of CXCL10 forms failed to stratify subjects based on treatment outcome to IFN-free regimens. However, a trend (statistically non-significant) towards elevated higher levels of total and long CXCL10 was observed pre-treatment in subjects who relapsed. All forms of CXCL10 decreased rapidly following treatment initiation and were again elevated in subjects who experienced HCV relapse, indicating that CXCL10 production may be associated with active viral replication. While soluble DPP4 (sDPP4) and NH2-truncated CXCL10 concentrations were highly correlated, on-treatment sDPP4 levels and activity declined more slowly than CXCL10, suggesting differential regulation. These data suggest post-translationally modified forms of CXCL10 will not support the prediction of treatment outcome in HCV GT1 subjects treated with SOF/RBV.
authors.affiliation: Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States of America; Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States of America; Critical Care Medicine Department, NIH, Bethesda, MD, United States of America.
authors.forename: Eric G
authors.initials: EG
authors.lastname: Meissner
authors.affiliation: The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Decalf
authors.affiliation: The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France.
authors.forename: Armanda
authors.initials: A
authors.lastname: Casrouge
authors.affiliation: Critical Care Medicine Department, NIH, Bethesda, MD, United States of America.
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States of America; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America.
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
authors.affiliation: The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France; Center for Human Immunology, Institut Pasteur, Paris, France.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
authors.affiliation: The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; INSERM U818, Paris, France; Center for Human Immunology, Institut Pasteur, Paris, France.
authors.forename: Darragh
authors.initials: D
authors.lastname: Duffy
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use; D054357:Chemokine CXCL10 / Q000097:blood* / Q000235:genetics; D003289:Convalescence; D018819:Dipeptidyl Peptidase 4 / Q000097:blood* / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D007372:Interferons; D008297:Male; D011499:Protein Processing, Post-Translational; D012008:Recurrence; D012254:Ribavirin / Q000627:therapeutic use; D000069474:Sofosbuvir / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D005449:Fluorenes; C586541:ledipasvir; D012254:Ribavirin; D007372:Interferons; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000069474:Sofosbuvir