Differential virus‐specific CD8⁺ T‐cell epitope repertoire in hepatitis C virus genotype 1 versus 4

Abstract

Virus-specific CD8 T-cell responses play an important role in the outcome of hepatitis C virus (HCV) infection. To date, most HCV-specific CD8 T-cell epitopes have been defined in HCV genotype 1 infection. In contrast, the HCV genotype 4-specific CD8 T-cell response is poorly defined. Here, we analysed whether known HCV-specific CD8 T-cell epitopes are also recognized in HCV genotype 4-infected patients and set out to identify the first HCV genotype 4-specific CD8 T-cell epitopes. We studied patients chronically infected with HCV genotype 1 (n = 20) or 4 (n = 21) using 91 well-described HCV-specific epitope peptides. In addition, we analysed 24 genotype 4-infected patients using 40 epitope candidates predicted using an in silico approach. HCV-specific CD8 T-cell responses targeting previously described epitopes were detectable in the majority of genotype 1-infected patients (11 of 20). In contrast, patients infected with HCV genotype 4 rarely targeted these epitopes (4 of 21; P = .0247). Importantly, we were able to identify eight novel HCV genotype 4-specific CD8 T-cell epitopes. Only one of these epitopes was shared between genotype 1 and genotype 4. These results indicate that there is little overlap between CD8 T-cell repertoires targeting HCV genotype 1 and 4. Prophylactic vaccination studies based on HCV genotype 1 are currently underway. However, in countries with the highest prevalence of HCV infection, such as Egypt, most patients are infected with HCV genotype 4. Thus, prophylactic vaccination strategies need to be adapted to HCV genotype 4 before their application to regions where HCV genotype 4 is endemic.

Adaptive Immune Response against Hepatitis C Virus

“…Indeed, CD8+ T cell epitopes that were induced by this vaccination regimen and targeted immunodominant HCV-specific epitopes displayed a limited capacity to cross-recognize viral variants circulating in the population [144]. This interpretation is also in line with the finding that the epitope repertoire between HCV genotype 1 and genotype 3 or 4, respectively, display little overlap [145,146]. Thus, current research addresses novel adjuvant formulations such as the use of MHC class II invariant chain-adjuvanted viral vectors, enhancing the peak magnitude, breath, and proliferative capacity of HCV-specific T cells induced by the ChAd3-HCV1b-NS prime/MVA-HCV-1b-NS boost vaccine in healthy volunteers [147].…”

Viral vectored hepatitis C virus vaccines generate pan-genotypic T cell responses to conserved subdominant epitopes

“…Immunodominant CD4 + and CD8 + T cell epitopes in variable viral regions display limited cross reactivity between HCV genotypes (30,42,44,45). The exclusion of variable HCV sequences containing immunodominant epitopes from an HCV immunogen may increase the targeting of subdominant epitopes by naïve T cells and therefore generate a vaccine-induced T cell response targeting subdominant epitopes that lie in conserved viral regions.…”

Hepatitis C Virus Vaccine: Challenges and Prospects

“…However, cross-reactive nAbs that are capable of targeting isolates from different genotypes have been described in several studies [102], thus highlighting that this challenge can be overcome. Epitope variability also leads to genotype-specific cellular responses for example Luxenburger et al [103] have recently shown CD8+ T cells from individuals chronically infected with a Gt4 HCV isolate failed to recognize Gt1 derived epitopes. Limited intergenotypic cross-reactivity of Gt3 HCV-specific T cells has also been reported in patients that successfully cleared Gt3 infections [104].…”