Dynamics of Genome Change in the E2/NS1 Region of Hepatitis C Virus in Vivo

Higashi, Yasuyuki; Kakumu, Shinichi; Yoshioka, Kentaro; Wakita, Takaji; Mizokami, Masashi; Ohba, Ken‐ichi; Ito, Yuji; Ishikawa, Tetsuya; Takayanagi, Masahiro; Nagai, Yuya

doi:10.1006/viro.1993.1641

Cited by 116 publications

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“…[11][12][13]29 Sequence analysis of cDNA clones derived from PCR products from individual patients has provided important information on the genetic variability of HCV HVR1. 6,7,11,12,17,30,31 However, taking into account the quasispecies nature of HCV and the marked heterogeneity of patients with chronic HCV infection, sequence analysis of a large number of clones would be necessary for accurate assessment of the role of viral heterogeneity in the pathogenesis of the disease and its response to therapy, but this methodology cannot easily be applied to studies involving a large number of patients. This limitation can partially be solved by using alternative indirect methods, such as SSCP analysis of amplified DNA products.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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In patients with chronic hepatitis C, the influence of the genetic heterogeneity of the hepatitis C virus (HCV) on the progression of liver disease and on the responsiveness to interferon therapy is a matter of controversy. In this study we evaluated the genetic complexity of HCV by singlestrand conformation polymorphism (SSCP) analysis of amplicons from the hypervariable region 1 (HVR1) in 168 patients with chronic genotype 1b HCV infection, of whom 122 received a single course of interferon therapy (3 MU, three times weekly for 6 months). No correlation was observed between the degree of genetic complexity of HCV (indicated by the number of bands in the SSCP assay) and patient age, serum alanine aminotransferase activity, or serum HCV-RNA concentration, measured by competitive polymerase chain reaction. HCV genomic complexity was not related to gender nor to the presumed source of infection. The number of SSCP bands detected in serum samples from patients with chronic hepatitis, either mild (8.1 ؎ 3.9), moderate (8.0 ؎ 3.3), or severe (9.2 ؎ 3.3), and in patients with liver cirrhosis, either compensated (8.0 ؎ 2.9), decompensated (6.3 ؎ 2.9), or with superimposed hepatocellular carcinoma (9.5 ؎ 2.9), was similar. The number of SSCP bands detected in patients with sustained response (7.5 ؎ 3.9), transient response (8.3 ؎ 2.9), or no response (8.2 ؎ 3.6) to interferon administration was similar as well. These observations suggest that the genetic complexity of hypervariable region (HVR1) of HCV, as estimated by SSCP analysis, is not related to the severity of liver injury nor to the type of response to interferon therapy. The hepatitis C virus (HCV) is an RNA virus that replicates with a high rate of mutation, 1 which is particularly evident in the hypervariable region 1 (HVR1) of the N-amino terminal region of the second envelope domain of the viral genome. 2,3 Under the influence of environmental factors, continuous viral mutation gives raise to a mixed and changing population of mutants, which is known as quasispecies. 4 As in infections with other RNA viruses, the quasispecies nature of HCV 5 may have important biological implications concerning viral persistence, pathogenicity, and resistance to antiviral agents. However, attempts aimed to define the relationship between clinical aspects of chronic HCV infection and the genetic heterogeneity of the infecting virus have provided conflicting results.By sequence analysis of HVR1, greater nucleotide sequence diversity between HCV variants was shown in isolates from patients with more advanced liver disease, 6 but this finding has not been confirmed by others. 7 Studies based on singlestrand conformational polymorphism (SSCP) analysis of HVR1 derived amplicons have also provided controversial data. In 1995, Koizumi et al. 8 found that the viral populations were more heterogeneous in patients with hepatic cirrhosis or hepatocellular carcinoma than in those with chronic hepatitis, but other studies did not disclose a clear association between the degree of HCV qu...

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Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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“…29 Although mutations occur throughout the entire genome of HCV, 30,31 most studies have focused on the quasispecies nature of the HVR1, which is located at the N-terminus of the E2/NS1 region. 32 Changes in this E2 domain presumably result from pressure from variantspecific neutralizing antibody, 33 virus-specific CD8ϩ CTL response, and/or antiviral therapy. 34 Variants that dominate over time presumably have survival advantage over those that are lost, in a ''Darwinian'' process that results in constant change in viral species.…”

Section: Discussionmentioning

confidence: 99%

Evolution of hepatitis C virus quasispecies in patients with severe cholestatic hepatitis after liver transplantation

et al. 1999

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Evolution of hepatitis C quasispecies may be one mechanism by which fibrosing cholestatic hepatitis develops after liver transplantation. In this study, we compared changes in quasispecies complexity and/or divergence in (1) hepatitis C-infected immunosuppressed transplant recipients and in immunocompetent controls; (2) transplant recipients with mild recurrence, and in those with the most severe form of posttransplantation recurrence. Quasispecies were measured in 12 hepatitis C-infected patients pretransplantation and posttransplantation (6 with mild and 6 with severe recurrence), and in 5 immunocompetent patients with similar follow-up, and characterized by heteroduplex mobility and sequence analysis of the hypervariable region. Although the number of variants (complexity) did not change with time in either group, there was a qualitative change in the variants with time (divergence) in immunocompromised, but not in immunocompetent patients. These changes were most marked with severe recurrence, and preceded the development of severe disease. Phylogenetic analysis confirmed that most posttransplantation variants were unrelated to those detected pretransplantation. These observations suggest that in the absence of immune suppression, there is minor evolution of quasispecies. With immune suppression, divergence of quasispecies is enhanced, resulting in selection/emergence of many new variants, particularly in those with fibrosing cholestatic hepatitis. Thus, quasispecies may influence disease progression in immune suppressed populations. (HEPATOLOGY 1999;30: 1513-1520.)Hepatitis C virus (HCV)-related end-stage liver disease has become the leading indication for liver transplantation in the majority of transplant centers. 1 Unfortunately, recurrence of infection is universal 2 and recurrent HCV disease is the most common cause of chronic hepatitis after transplantation. 3,4 Although within 1 year of follow-up only about 50% of transplant recipients will develop histological evidence of HCV-related disease, 3,5 with longer follow-up, the majority of patients evolve to a slowly progressive form of chronic hepatitis. 6,7 There is a subset of patients, albeit the minority, who develops an extremely severe form of posttransplantation hepatitis, characterized by cholestasis and progressive fibrosing hepatitis, which typically results in allograft failure in less than 1 year. 8,9 Such cases have been compared with the fibrosing cholestatic variant of hepatitis B, also described in the setting of transplantation. 10

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“…3). Sequence analysis revealed that (i) several quasispecies of virus co-existed simultaneously in a single individual (Higashi et al, 1993), (ii) the low density particles contained additional multiple base changes within the HVR that were clustered between amino acids 401 and 407. Furthermore, these base changes were accumulative (e.g.…”

confidence: 99%

Association of hepatitis C virus particles with immunoglobulin: a mechanism for persistent infection

Choo

Cho

et al. 1995

Journal of General Virology

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The physical properties of hepatitis C virus (HCV) particles were determined by ultracentrifugation on 20-60 % isopycnic sucrose density gradients. We report that (i) two populations of HCV particles were found in the sera of patients with chronic HCV infection [at high density (1.186-1.213 g/ml) and at low density (1.099-1.127 g/ml)], (ii) virus particles with high density values were associated with immunoglobulin, and (iii) virus particles with low density values accumulated base changes within a hypervariable region (HVR) of the E2 envelope domain of the RNA genome. The results indicate that base changes within the HVR of E2 lead to the accumulation ofimmunoglobulin-free virus particles. Therefore, these findings imply that persistent HCV infection is established as a consequence of sequence variation in the E2 envelope domain.

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Dynamics of Genome Change in the E2/NS1 Region of Hepatitis C Virus in Vivo

Cited by 116 publications

References 0 publications

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

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

Evolution of hepatitis C virus quasispecies in patients with severe cholestatic hepatitis after liver transplantation

Association of hepatitis C virus particles with immunoglobulin: a mechanism for persistent infection

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