IRES complexity before IFN-alpha treatment and evolution of the viral load at the early stage of treatment in peripheral blood mononuclear cells from chronic hepatitis C patients

• Published in: Journal of medical virology 2007-03, Vol.79 (3), p.242-253
• Main Authors: Thélu, M.A., Leroy, V., Ramzan, M., Dufeu-Duchesne, T., Marche, P., Zarski, J.P.
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions; Adult; Antiviral Agents; Antiviral Agents - therapeutic use; Base Sequence; Biological and medical sciences; Cells, Cultured; Female; Fundamental and applied biological sciences. Psychology; Genome, Viral; HCV-IRES; Hepacivirus; Hepacivirus - classification; Hepacivirus - genetics; Hepacivirus - physiology; Hepatitis C virus; Hepatitis C, Chronic; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - virology; Human health and pathology; Human viral diseases; Humans; Hépatology and Gastroenterology; Infectious diseases; Interferon Alfa-2a; Interferon-alpha - therapeutic use; Leukocytes, Mononuclear; Leukocytes, Mononuclear - virology; Life Sciences; Male; Medical sciences; Microbiology; Middle Aged; Miscellaneous; Molecular Sequence Data; Mutation; Nucleic Acid Conformation; PBMCs; Polymorphism, Genetic; quasi- species; Recombinant Proteins; RNA, Viral; RNA, Viral - genetics; Sequence Analysis, DNA; variants; Viral diseases; Viral hepatitis; Viral Load; Virology
• ISSN: 0146-6615; 1096-9071
• DOI: 10.1002/jmv.20792

At the early stage of treatment, IFN alpha‐2a induces inhibition of HCV replication. The viral load reflects mainly the degradation rate of the viruses. However, differences in the behavior of the viral population depend on changes, which occurred in the HCV‐IRES genome. In this study, cloning and sequencing strategies permitted the generation of a large number of IRES sequences from the PBMCs of 18 patients (5 women, 13 men) with chronic hepatitis C. The HCV IRES appeared to be highly conserved structurally. However, some variability was found between the different isolates obtained: 467 substitutions with a median of 7 variants/patients. No relationship was observed between pre‐treatment IRES complexity and the viral load at the beginning. However, on review of the evolution of viral load in the PBMCs during the first 3 days of IFN alpha‐2a treatment, patients could be classified into two groups: Group 1, in which the viral population continued to replicate and Group 2, in which the viral load decreased significantly (P = 0.01727). Positioning of the mutations on the predicted IRES secondary structure showed that the distribution of the mutations and their apparition frequency were different between the two groups. At the early stage of treatment, IFN alpha‐2a was efficient in reducing the viral replication in a significant number of patients; mechanisms of response might affect the virus directly. However, pre‐treatment genomic variations observed in the 5′NCR of HCV were not a parameter of a later response to antiviral therapy in chronic hepatitis C patients. (244) J. Med. Virol. 79:242–253, 2007. © 2007 Wiley‐Liss, Inc.