title: Cytokine/chemokine patterns connect host and viral characteristics with clinics during chronic hepatitis C.
abstract: BACKGROUND
  In chronic hepatitis C virus (HCV) infection, liver tissue pathology and HCV genotype are important determinants of clinical and/or treatment-related outcome. Although consistent epidemiological and/or molecular-biological clues derived from different studies on single virus-host interactions are meanwhile published, the in vivo transcriptional responses and cellular pathways affected in >1 key aspects of the disease or treatment process are far from being understood.
  
  
  METHODS
  Microarray analysis was performed in peripheral whole blood (PB) samples from 36 therapy-naïve HCV-infected patients with known liver histology. Linear regression analysis identified gene expression profiles significantly correlating (P < 0.015) with ≥1 out of 7 variables: sustained viral response (SVR), viral non-response (NR), end of treatment viral response (ETR), viral breakthrough (VB), HCV genotype (Gt. 1 vs. Gt. 2/3), stage of hepatic fibrosis [St. 0/1 vs. St. 2/3/4] and grade of hepatic inflammation (Gr. 0/1 vs. Gr. 2/3/4). Correlation values across all seven contrasts were considered for hierarchical clustering (HCL).
  
  
  RESULTS
  A total of 1,697 genes showed ≥1 significant correlation results and genes involved in cell differentiation (183), immune response (53), and apoptosis (170) were leading fractions. HCL grouped the genes into six major clusters. Functional annotation analysis using DAVID (http://david.abcc.ncifcrf.gov) revealed that expression profiles that best linked these variables were highly enriched in cytokine/chemokine activity (Fisher-exact P < 0.0001) and specific biological module-centric algorithms finally led our focus on four out of fifty-three immune response genes: SMAD family member 3 (SMAD3), interleukin 1 receptor accessory protein (IL1RAP), tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), and chemokine 'C-C motif' receptor 5 (CCR5). Of those, TNFRSF1A and CCR5 showed significant correlation with two out of seven variables based on microarray and/or quantitative real-time polymerase chain reaction (qRT-PCR) data.
  
  
  CONCLUSIONS
  We identified molecular targets of the innate and adaptive immune system and validated their transcriptional specificity in vivo suggesting significant involvement in two unique outcomes during HCV treatment.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Germany. antonios.katsounas@uk-essen.de
authors.forename: Antonios
authors.initials: A
authors.lastname: Katsounas
authors.forename: Martin
authors.initials: M
authors.lastname: Trippler
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lempicki
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.forename: Joerg F
authors.initials: JF
authors.lastname: Schlaak
mesh_terms: D000465:Algorithms; D000998:Antiviral Agents / Q000627:therapeutic use; D017209:Apoptosis; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005500:Follow-Up Studies; D005814:Genes, Viral; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000628:therapy / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000821:virology; D016898:Interferon-alpha / Q000627:therapeutic use; D016014:Linear Models; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D018925:Chemokines; D016207:Cytokines; D016898:Interferon-alpha; D012367:RNA, Viral; D019713:Receptors, CCR5; D047888:Receptors, Tumor Necrosis Factor, Type I; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C506235:TNFRSF1A protein, human