title: Hepatitis C Virus Deletion Mutants Are Found in Individuals Chronically Infected with Genotype 1 Hepatitis C Virus in Association with Age, High Viral Load and Liver Inflammatory Activity.
abstract: Hepatitis C virus (HCV) variants characterized by genomic deletions in the structural protein region have been sporadically detected in liver and serum of hepatitis C patients. These defective genomes are capable of autonomous RNA replication and are packaged into infectious viral particles in cells co-infected with the wild-type virus. The prevalence of such forms in the chronically HCV-infected population and the impact on the severity of liver disease or treatment outcome are currently unknown. In order to determine the prevalence of HCV defective variants and to study their association with clinical characteristics, a screening campaign was performed on pre-therapy serum samples from a well-characterized cohort of previously untreated genotype 1 HCV-infected patients who received treatment with PEG-IFNα and RBV. 132 subjects were successfully analyzed for the presence of defective species exploiting a long-distance nested PCR assay. HCV forms with deletions predominantly affecting E1, E2 and p7 proteins were found in a surprising high fraction of the subjects (25/132, 19%). Their presence was associated with patient older age, higher viral load and increased necroinflammatory activity in the liver. While the presence of circulating HCV carrying deletions in the E1-p7 region did not appear to significantly influence sustained virological response rates to PEG-IFNα/RBV, our study indicates that the presence of these subgenomic HCV mutants could be associated with virological relapse in patients who did not have detectable viremia at the end of the treatment.
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cheroni
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Donnici
authors.affiliation: A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milan, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Aghemo
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Balistreri
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Bianco
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Zanoni
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Pagani
authors.affiliation: A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Soffredini
authors.affiliation: A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: D'Ambrosio
authors.affiliation: Division of Hepatology, Ospedale San Giuseppe IRCCS Multimedica, Università degli Studi di Milano, Milan, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Rumi
authors.affiliation: A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Colombo
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy; DISCCO, Department of Clinical Sciences and Community Health Università degli Studi di Milano, Milan, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Petra
authors.initials: P
authors.lastname: Neddermann
authors.affiliation: INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000821:virology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D008099:Liver / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D015995:Prevalence; D011994:Recombinant Proteins / Q000627:therapeutic use; D012008:Recurrence; D012254:Ribavirin / Q000627:therapeutic use; D017384:Sequence Deletion; D014759:Viral Envelope Proteins / Q000235:genetics; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics*; D000086082:Viroporin Proteins
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C087035:E1 protein, Hepatitis C virus; C088369:p7 protein, Hepatitis C virus; D000086082:Viroporin Proteins; C417083:peginterferon alfa-2b