Hepatitis C virus – T‐cell responses and viral escape mutations

Abstract

IrelandHepatitis C virus (HCV) is a small, enveloped RNA virus and the number of HCV-infected individuals worldwide is estimated to be approximately 170 million. Most HCV infections persist, with up to 80% of all cases leading to chronic hepatitis associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma. HCV-host interactions have a crucial role in viral survival, persistence, pathogenicity of infection, and disease progression. Maintenance of a vigorous, sustained cellular immune response recognizing multiple epitopes is essential for viral clearance. To escape immune surveillance, HCV alters its epitopes so that they are no-longer recognized by T cells and neutralizing antibodies, in addition to interfering with host cell cellular components and signaling pathways. The generation of escape variants is one of the most potent immune evasion strategies utilized by HCV. A large body of evidence suggests that single or multiple mutations within HLA-restricted epitopes contribute to viral immune escape and establishment of viral persistence. Further elucidation of the molecular mechanisms underlying immune escape will aid in the design of novel vaccines and therapeutics for the disease.

Statistical Linkage Analysis of Substitutions in Patient-Derived Sequences of Genotype 1a Hepatitis C Virus Nonstructural Protein 3 Exposes Targets for Immunogen Design

“…We compiled a list of epitopes (see Table S5 in the supplemental material) presented by the individual alleles within these haplotypes using the data from reference 58. A worst-case approach was pursued; i.e., it was assumed that a single substitution in the epitope can eliminate epitope presentation or abrogate recognition by T cells, resulting in immune escape (15,16). Moreover, we included from the database only epitopes that were exclusively comprised of wild-type residues.…”

“…On the other hand, some reports indicate the importance of a T cell-based vaccine against HCV due to strong association of broadly directed immune responses involving both CD4 ϩ and CD8 ϩ T cells with viral clearance (13,14). However, due to the high variability of HCV, point substitutions in T-cell epitopes can abrogate the associated response by interfering with presentation or recognition mechanisms (15,16). This suggests that a vaccine should induce T-cell responses against HCV epitopes that are highly conserved, i.e., epitopes where the frequency of single substitutions is low within circulating viral strains, suggesting that such substitutions might compromise viral fitness.…”

T cell epitope redundancy: cross-conservation of the TCR face between pathogens and self and its implications for vaccines and autoimmunity

“…It is well known that HCV epitopes mutate over the course of infection to decrease MHC binding. This has been well-defined for CTL epitopes, but is less well defined for CD4+ T cell epitopes [60][61][62]. However, in the case of the HCV epitope described by Losikoff et al [42], the HCV genomic sequences appears to contain the same TCR-facing residues as highly prevalent autologous T cell epitopes, so as to acquire the potential to drive Treg responses in an HLA-diverse population.…”

Hepatitis C Virus Suppresses C9 Complement Synthesis and Impairs Membrane Attack Complex Function

“…People with chronic HCV infection often progress to cirrhosis and liver cancer. There is currently no vaccine for HCV, but available treatments can eradicate the virus and slow or stop disease progression in some chronically infected patients (1,2).…”