Hepatitis C virus 5′ untranslated region variability correlates with treatment outcome

Hepatitis C virus (HCV) variability affects viral–host interactions. We analysed HCV 5′untranslated region (5′UTR) in sera and peripheral blood mononuclear cells (PBMC) from chronic hepatitis C patients undergoing antiviral treatment. We studied 139 patients treated with pegylated interferon and ribavirin. The primary endpoint was a sustained virological response (SVR) defined as negative HCV RNA level 24 weeks after the end of therapy. 5′UTR was analysed by single‐strand conformational polymorphism (SSCP) and sequencing. The pretreatment SSCP pattern in serum and PBMC differed in 26 (18.7%) patients. During therapy, the SSCP pattern remained stable in 65 (60.8%) patients, number of bands declined in 16 (15.0%), and in 18 (16.8%) patients, changes were qualified as ‘shift’ indicating change in band positions. In univariate analysis, there was a significant (P ≤ 0.05) positive association between SVR and pretreatment serum and PBMC dissimilarities, initial viral load <106 IU/mL, IL‐28B CC genotype of the rs12979860 single nucleotide polymorphism and change in the SSCP band pattern (either ‘shift’ or decline) In multivariable analysis, only low initial viral load, IL‐28B genotype, and changes in the SSCP band pattern were independent factors associated with SVR. In conclusion, stability of 5′UTR correlated with infection persistence, while changes correlated with SVR.

[1]  A. Neumann,et al.  Response Prediction in Chronic Hepatitis C by Assessment of IP-10 and IL28B-Related Single Nucleotide Polymorphisms , 2011, PloS one.

[2]  K. Shianna,et al.  IL28B genotype is associated with differential expression of intrahepatic interferon‐stimulated genes in patients with chronic hepatitis C , 2010, Hepatology.

[3]  J. Eschbacher,et al.  Activation of brain macrophages/microglia cells in hepatitis C infection , 2010, Gut.

[4]  William M. Lee,et al.  Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. , 2009, The New England journal of medicine.

[5]  David B. Goldstein,et al.  Genetic variation in IL28B and spontaneous clearance of hepatitis C virus , 2009, Nature.

[6]  A. Koike,et al.  Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C , 2009, Nature Genetics.

[7]  Thomas Berg,et al.  IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy , 2009, Nature Genetics.

[8]  Jacques Fellay,et al.  Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance , 2009, Nature.

[9]  Ming‐Lung Yu,et al.  Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: A randomized trial , 2008, Hepatology.

[10]  J. Rakela,et al.  Selection of different 5′ untranslated region hepatitis C virus variants during post‐transfusion and post‐transplantation infection , 2006, Journal of viral hepatitis.

[11]  J. Rakela,et al.  Analysis of hepatitis C virus quasispecies transmission and evolution in patients infected through blood transfusion. , 2004, Gastroenterology.

[12]  G. Klintmalm,et al.  Hepatitis C virus quasi-species dynamics predict progression of fibrosis after liver transplantation. , 2004, The Journal of infectious diseases.

[13]  E. Drouet,et al.  Lack of clinical significance of variability in the internal ribosome entry site of hepatitis C virus , 2004, Journal of medical virology.

[14]  Michael Zuker,et al.  Mfold web server for nucleic acid folding and hybridization prediction , 2003, Nucleic Acids Res..

[15]  J. Pawlotsky,et al.  Quasispecies heterogeneity and constraints on the evolution of the 5' noncoding region of hepatitis C virus (HCV): relationship with HCV resistance to interferon-alpha therapy. , 2002, Virology.

[16]  Angelo Balestrieri,et al.  Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  H J Alter,et al.  The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. , 2000, Science.

[18]  C. Pasquier,et al.  Longitudinal analysis of hepatitis C virus replication and liver fibrosis progression in renal transplant recipients. , 2000, The Journal of infectious diseases.

[19]  J. Rakela,et al.  Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocytes/macrophages and lymphocytes. , 2000, The Journal of infectious diseases.

[20]  J. Rakela,et al.  Uneven Distribution of Hepatitis C Virus Quasispecies in Tissues from Subjects with End-Stage Liver Disease: Confounding Effect of Viral Adsorption and Mounting Evidence for the Presence of Low-Level Extrahepatic Replication , 2000, Journal of Virology.

[21]  Mengji Lu,et al.  Selection of genetic variants of the 5′ noncoding region of hepatitis C virus occurs only in patients responding to interferon α therapy , 1999, Journal of medical virology.

[22]  H. Hsu,et al.  Decreased diversity of hepatitis C virus quasispecies during bone marrow transplantation , 1999, Journal of medical virology.

[23]  S. Ampurdanés,et al.  Relationship of the genomic complexity of hepatitis C virus with liver disease severity and response to interferon in patients with chronic HCV genotype 1b interferon , 1999, Hepatology.

[24]  J. Rakela,et al.  Detection of hepatitis C virus replication in peripheral blood mononuclear cells after orthotopic liver transplantation. , 1998, Transplantation.

[25]  J. Rakela,et al.  Hepatitis C virus quasispecies in patients infected with HIV-1: correlation with extrahepatic viral replication. , 1998, Virology.

[26]  C. Trépo,et al.  In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: influence of viral load, viral genotype, and cell phenotype. , 1998, Blood.

[27]  H. Thomas,et al.  Comparison of the rate of sequence variation in the hypervariable region of E2/NS1 region of hepatitis C virus in normal and hypogammaglobulinemic patients , 1998, Hepatology.

[28]  N. Enomoto,et al.  Nucleotide sequence variations in the internal ribosome entry site of hepatitis C virus‐1b: No association with efficacy of interferon therapy or serum HCV‐RNA levels , 1997, Hepatology.

[29]  L. Corey,et al.  Tracking hepatitis C virus quasispecies major and minor variants in symptomatic and asymptomatic liver transplant recipients , 1996, Journal of virology.

[30]  M. Honda,et al.  Stability of a stem-loop involving the initiator AUG controls the efficiency of internal initiation of translation on hepatitis C virus RNA. , 1996, RNA.

[31]  P. Simmonds,et al.  Variation of the hepatitis C virus 5' non-coding region: implications for secondary structure, virus detection and typing. The International HCV Collaborative Study Group. , 1995, The Journal of general virology.

[32]  H. Fusamoto,et al.  Hepatitis C viral complexity detected by single-strand conformation polymorphism and response to interferon therapy. , 1995, Gastroenterology.

[33]  A. Siddiqui,et al.  A conserved helical element is essential for internal initiation of translation of hepatitis C virus RNA , 1994, Journal of virology.

[34]  S. Mishiro,et al.  Superinfection of chimpanzees carrying hepatitis C virus of genotype II/1b with that of genotype III/2a or I/1a , 1994, Hepatology.

[35]  J. Berzofsky,et al.  An epitope in hepatitis C virus core region recognized by cytotoxic T cells in mice and humans , 1994, Journal of virology.

[36]  R. Miller,et al.  Lack of protective immunity against reinfection with hepatitis C virus. , 1993, Science.

[37]  L. Ping,et al.  Secondary structure of the 5' nontranslated regions of hepatitis C virus and pestivirus genomic RNAs. , 1992, Nucleic acids research.

[38]  Y. Ito,et al.  Genetic drift of hepatitis C virus during an 8.2-year infection in a chimpanzee: variability and stability. , 1992, Virology.

[39]  R. Purcell,et al.  Sequence analysis of the 5' noncoding region of hepatitis C virus. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[40]  A. Weiner,et al.  Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution , 1992, Journal of virology.

[41]  A. Prince,et al.  Immunity in hepatitis C infection. , 1992, The Journal of infectious diseases.

[42]  A. Nomoto,et al.  Internal ribosome entry site within hepatitis C virus RNA , 1992, Journal of virology.

[43]  R. Purcell,et al.  Nucleotide sequence and mutation rate of the H strain of hepatitis C virus. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[44]  P. Barr,et al.  Genetic organization and diversity of the hepatitis C virus. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Rakela,et al.  Infection of primary human macrophages with hepatitis C virus in vitro: induction of tumour necrosis factor-alpha and interleukin 8. , 2004, The Journal of general virology.

[46]  G. Klintmalm,et al.  Hepatitis C Virus QuasiSpecies Dynamics Predict Progression of Fibrosis after Liver Transplantation , 2004 .

[47]  J. Rakela,et al.  Infection of primary human macrophages with hepatitis C virus in vitro: Induction of tumour necrosis factor-α and interleukin 8 , 2004 .

[48]  G. McCaughan,et al.  Post-transplant quasispecies pattern remains stable over time in patients with recurrent cholestatic hepatitis due to hepatitis C virus. , 2000, Journal of hepatology.

[49]  H. Toyoda,et al.  Quasispecies nature of hepatitis C virus and response to alpha interferon: significance as a predictor of direct response to interferon. , 1997, Journal of hepatology.

[50]  J. Holland,et al.  Rapid evolution of RNA viruses. , 1987, Annual review of microbiology.

[51]  E. Domingo,et al.  The quasispecies (extremely heterogeneous) nature of viral RNA genome populations: biological relevance--a review. , 1985, Gene.