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

Abstract

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.

Detection of Inhibition of Bovine Viral Diarrhea Virus by Aromatic Cationic Molecules

“…The screening method described in this research has the potential to identify compounds that exhibit a mechanism of action beyond the scope of the subgenomic replicon assay. As the RNA-dependent RNA polymerase of HCV lacks proofreading ability and exhibits a (9), a number of antiviral agents directed at multiple targets will be required to reduce or eliminate HCV quasispecies that have developed resistance to other drugs (5). If the replicon assay is used as the sole determinant in selecting HCV antiviral candidates, then compounds with antiviral targets involving viral attachment and entry into cells, packaging of viral RNA within the virion, or viral release will be regrettably overlooked.…”

Wide Range of Quasispecies Diversity during Primary Hepatitis C Virus Infection

“…nucleotide substitutions per site per year (2,3,6,10,16,29,60). Assuming the highest reported mutation rate (calculated for the 81 nucleotides of HVR-1) (6) and a 20-day period of viral replication prior to sample collection, an upper bound estimate of pairwise genetic distance of 0.47% could be attributed to de novo mutations occurring following transmission.…”

Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX™ vaccine: A phase I study in healthy volunteers

“…15 This failure of the host immune response to eliminate HCV may be due in part to the rapid generation of viral variants during the course of infection 16 and weak immunogenicity resulting from low level viral replication. 17 Another mechanism is thought to involve the NS3/4a protease of HCV which is responsible for inhibiting the induction of type 1 interferons. 18 Current treatment of chronic HCV infection consists of the combination of pegylated interferon-α and the nucleoside analogue ribavirin, but sustained viral clearance only occurs in about 55% of recipients.…”