title: Hepatitis C virus load and expression of a unique subset of cellular genes in circulating lymphoid cells differentiate non-responders from responders to pegylated interferon alpha-ribavirin treatment.
abstract: Based on investigations of liver biopsy material, certain cellular genes have been implicated as correlates of success or failure to interferon alpha-ribavirin (IFN/RBV) therapy against hepatitis C. The current study aimed at determining whether expression of host genes thought to be relevant to HCV replication in the liver would be correlated with HCV infection status in peripheral blood mononuclear cells (PBMCs) and also with patient responsiveness to IFN/RBV treatment. Therefore, PBMCs from patients with chronic hepatitis C responding (n = 35) or not (n = 49) to IFN/RBV and from healthy controls (n = 15) were evaluated for HCV RNA load and cellular gene expression. Non-responders had 3- to 10-fold higher basal levels of interleukin (IL)-8, IFN-stimulated gene 15 (ISG15), 2',5'-oligoadenylate synthetase (OAS), and Toll-like receptors (TLR)-4, -5, and -7 compared to responders. Non-responders with similar post-treatment follow-ups as responders persistently expressed 6- to 20-fold greater levels of IL-8, ISG15, and OAS after therapy. Higher expression of IFN-α, IFN-γ, and IFN-λ was found in PBMCs of individuals achieving sustained virological response, either before or after therapy. Pre-treatment HCV RNA loads in PBMCs of non-responders were significantly higher (P = 0.016) than those of responders. In conclusion, the data indicate that immune cells of responders and non-responders to IFN/RBV therapy exhibited significantly different virological and host gene expression profiles. Elevated baseline HCV loads and TLR-4, -5, and -7 levels, and persistently high levels of IL-8, ISG15, and OAS were correlated with IFN non-responsiveness. The results warrant further investigations on the utilization of PBMCs for predicting success or failure to IFN-based therapies.
authors.affiliation: Molecular Virology and Hepatology Research Group, Faculty of Medicine, Memorial University, St. John's, NL, Canada.
authors.forename: Tram N Q
authors.initials: TN
authors.lastname: Pham
authors.forename: Dolly M H
authors.initials: DM
authors.lastname: Lin
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Mulrooney-Cousins
authors.forename: Norma D
authors.initials: ND
authors.lastname: Churchill
authors.forename: Arleta
authors.initials: A
authors.lastname: Kowala-Piaskowska
authors.forename: Iwona
authors.initials: I
authors.lastname: Mozer-Lisewska
authors.forename: Anna
authors.initials: A
authors.lastname: Machaj
authors.forename: Monika
authors.initials: M
authors.lastname: Pazgan-Simon
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Zalewska
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Simon
authors.forename: Dawn
authors.initials: D
authors.lastname: King
authors.forename: S Bharati
authors.initials: SB
authors.lastname: Reddy
authors.forename: Tomasz I
authors.initials: TI
authors.lastname: Michalak
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D016174:Hepacivirus / Q000276:immunology / Q000302:isolation & purification*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012367:RNA, Viral / Q000097:blood; D012254:Ribavirin / Q000627:therapeutic use*; D051193:Toll-Like Receptors / Q000096:biosynthesis; D016896:Treatment Outcome; D014452:Ubiquitins / Q000096:biosynthesis; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; D012367:RNA, Viral; D051193:Toll-Like Receptors; D014452:Ubiquitins; D012254:Ribavirin; C074034:ISG15 protein, human; D015088:2',5'-Oligoadenylate Synthetase