Comparison of the rate of sequence variation in the hypervariable region of E2/NS1 region of hepatitis C virus in normal and hypogammaglobulinemic patients

Booth, J; Kumar, Umesh; Webster, D. H.; Monjardino, J; Thomas, Howard

doi:10.1002/hep.510270134

Cited by 129 publications

(108 citation statements)

References 24 publications

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“…22 Several studies suggest that humoral immune pressure leads to selection of specific species that may be more capable of evading the host immune response. 23,24 Full sequence evaluation of clones would be necessary to evaluate specific humoral and cellular responses to epitopes derived from clonal variants. This has not yet been performed.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis cRNA quasispecies complexity in patients with alcoholic liver disease

et al. 1999

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Alcohol abuse is described as a major cofactor in the development of hepatitis C (HCV) associated liver disease and may play a role in the outcome of interferon-based treatment interventions. The association between HCV viral heterogeneity and alcohol has not been previously described. This study was designed to evaluate the quasispecies nature of the HCV population in patients with compensated and decompensated alcoholic liver disease, to test the hypothesis that alcoholics have greater complexity than matched nonalcoholic controls. A nonisotopic heteroduplex complexity assay (HCA) was first validated by comparison with results of quasispecies complexity determined by subcloning and sequencing of amplicon products from the E2/NS1 hypervariable coding region (HVR). Subsequently Hepatitis C virus (HCV) infection represents an important comorbidity in patients with alcohol abuse and alcoholic liver disease. Seroprevalence surveys have established that 8% to 45% of this cohort may have concomitant HCV antibodies suggestive of active, ongoing infection. 1 The combination of alcohol and HCV has been epidemiologically associated with increased risk of liver disease injury and progression. [2][3][4] Furthermore, there are limited data that suggest that interferon treatment response is also blunted in these patients. 5 The underlying pathophysiology that explains these differences has not yet been elucidated.Factors that may influence disease progression and treatment outcome include virus characteristics and host response. We have previously studied genotype distribution in patients with alcoholic liver disease and did not discern significant variation from nonalcoholic patients. Using a serologic method to assign genotypes, we did observe an increased percentage of untypeable viral isolates, which may be attributable to an altered immune response against type specific epitopes. 6 This observation raised the possibility that altered immunosurveillance might play a role in impaired viral clearance and might permit the development of a population of closely related variants.HCV is an RNA virus that lacks the ability to perform editing and correction in replication products. Therefore, it is capable of generating multiple mutant forms within an individual patient. These variants have been termed quasispecies. The envelope coding domain contains a hypervariable region that is most likely to show inefficient clearance of emerging quasispecies, though mutant emergence and selection may be seen in other coding domains as well. We hypothesized that quasispecies complexity may be increased in alcoholic patients compared with a nonalcoholic control group based on clinical observations of outcomes and interferon response rates. A rapid semiquantitative methodology to assess quasispecies complexity was developed and validated, and the hypothesis was tested in alcoholic patients and a matched control cohort. PATIENTS AND METHODS PatientsThe study cohort consisted of 20 patients with alcoholic liver disease and concomitant HCV infec...

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Section: Discussionmentioning

confidence: 99%

Hepatitis cRNA quasispecies complexity in patients with alcoholic liver disease

et al. 1999

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“…13,14,30,31 We conducted a longitudinal study of virus mutation in individual patients, rather than a cross-sectional study, as this is a more appropriate methodology for observing the natural history of virus-host interactions. Many earlier studies have included patients carrying a variety of HLA types, infected with differing HCV genotypes for varying periods of time.…”

Section: Discussionmentioning

confidence: 99%

“…Earlier studies have reported lower rates of coding mutation in antibody deficient compared with immunocompetent patients. 13,14 This has been interpreted as evidence that mutation in the HVR is selected by the host antibody response. However, a review of the data reveals a lower frequency of both cryptic and coding mutations in the antibody deficient patients when compared with the controls.…”

Section: Discussionmentioning

confidence: 99%

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

et al. 1999

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How Hepatitis C Virus (HCV) causes persistent infection is unknown. One hypothesis is that HCV evades the host immune response through mutation in immune epitopes. We have investigated mutations in the HCV genome to see if they cluster within immune epitopes; and we have studied the effect of antibody deficiency on mutation rates. We studied patients with chronic hepatitis C, 3 with antibody deficiency and 3 with normal immunity. Regions of the core and envelope genes of HCV, encoding cytotoxic (CTL), and B cell epitopes were sequenced at 2 time points, 2 years apart. The diversity of quasispecies increased with time. The HCV genetic mutation rate was higher than previously predicted. The cryptic nucleotide mutation rate in core was similar to that observed in envelope, suggesting that the error rate of the HCV RNA polymerase is similar in both regions. In contrast, the coding mutation rate was decreased in core and increased in envelope. No genetic mutation was seen in any of the core CTL epitopes despite detectable cellular responses. All patients had mutations within a previously described envelope CTL epitope but did not exhibit immune responses to either index or mutated peptides. There was no difference in mutation rates in any cellular or humoral epitopes between patients with antibody deficiency and normal immunity. Thus we have found no evidence that mutations were selected by T-lymphocytes or antibodies. These findings implicate alternative virushost interactions in the selection of HCV mutations.

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“…Also, antibodies may play a role here because an early antibody recognition of the hypervariable region 1 (HVR1) in the envelope E2 protein was correlated with virus clearance (Allander et al, 1997), and infection of chimpanzees could be inhibited by a human hyperimmune serum against HVR1 (Farci et al, 1996). In line with this are studies on the rate of HVR1 evolution that have suggested that the HVR1 region is under immune pressure exerted by neutralizing antibodies (Booth et al, 1998;Kato et al, 1993; Shimizu et al, 1994;Weiner et al, 1992). Nevertheless, by using infectious retroviral pseudotypes, a recent study has shown that neutralizing antibody responses early after infection do not seem to play a role in the resolution of an acute infection (Logvinoff et al, 2004 aspect is that HCV seems to have a wide cell tropism and can infect not only hepatocytes but also cells of the immune system (Bain et al, 2001;Sung et al, 2003).…”

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confidence: 97%

Hepatitis C virus population analysis of a single-source nosocomial outbreak reveals an inverse correlation between viral load and quasispecies complexity

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et al. 2004

Journal of General Virology

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The features of Hepatitis C virus (HCV) quasispecies within an envelope segment including the hypervariable region 1 were analysed at an early time point post-infection in seven patients that acquired HCV from a single common donor during a nosocomial outbreak. The grouping of patients according to viral load was reflected in the structure of the quasispecies. A higher viral load correlated with the presence of a predominant HCV genome and a corresponding lower quasispecies complexity. The quasispecies complexity itself was not correlated with HCV clearance or persistence. Thus, the relationship between an intrapatient HCV quasispecies and the clinical outcome of an HCV infection is more complex than previously anticipated. INTRODUCTIONHepatitis C virus (HCV) is an enveloped positive-strand RNA virus of the family Flaviviridae. Only about 15-30 % of HCV infections are spontaneously cleared, the remaining result in virus persistence with subsequent development of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (Alter et al., 1999). Because worldwide over 170 million people are infected carriers, HCV is a major health problem and a key issue in antiviral research.The mechanisms responsible for the high rate of viral persistence are thought to be the result of a complex host-virus interaction early after infection (Racanelli & Rehermann, 2003). However, little is known about these early virus and host determinants because the acute phase of infection is often asymptomatic and thus most diagnoses are made during the chronic stage, i.e. months or years after the events that determined the clinical course of the infection. While HCV induces strong humoral and cellular immune responses, their roles in virus clearance or persistence have not been fully elucidated. Studies in humans and chimpanzees indicate that a robust intrahepatic CD4 + and CD8 + T-cell response during the first weeks after infection is associated with viral clearance (Cooper et al., 1999;Major et al., 2004;Thimme et al., 2002). Also, antibodies may play a role here because an early antibody recognition of the hypervariable region 1 (HVR1) in the envelope E2 protein was correlated with virus clearance (Allander et al., 1997), and infection of chimpanzees could be inhibited by a human hyperimmune serum against HVR1 (Farci et al., 1996). In line with this are studies on the rate of HVR1 evolution that have suggested that the HVR1 region is under immune pressure exerted by neutralizing antibodies (Booth et al., 1998;Kato et al., 1993; Shimizu et al., 1994;Weiner et al., 1992). Nevertheless, by using infectious retroviral pseudotypes, a recent study has shown that neutralizing antibody responses early after infection do not seem to play a role in the resolution of an acute infection (Logvinoff et al., 2004 aspect is that HCV seems to have a wide cell tropism and can infect not only hepatocytes but also cells of the immune system (Bain et al., 2001;Sung et al., 2003). Another important feature is that HCV behaves in infected patients as a c...

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Comparison of the rate of sequence variation in the hypervariable region of E2/NS1 region of hepatitis C virus in normal and hypogammaglobulinemic patients

Cited by 129 publications

References 24 publications

Hepatitis cRNA quasispecies complexity in patients with alcoholic liver disease

Hepatitis cRNA quasispecies complexity in patients with alcoholic liver disease

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

Hepatitis C virus population analysis of a single-source nosocomial outbreak reveals an inverse correlation between viral load and quasispecies complexity

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