HCV genotype-3a T cell immunity: specificity, function and impact of therapy

Abstract

BackgroundHepatitis C virus (HCV) genotype-3a infection is now the dominant strain in South Asia and the UK. Characteristic features include a favourable response to therapy; the reasons for this are unknown but may include distinct genotype-3a-specific T cell immunity. In contrast to genotype-1 infection, T cell immunity to this subtype is poorly defined.ObjectivesThe aims of the study were to (1) define the frequency, specificity and cross-reactivity of T cell immunity across the whole viral genome in genotype-3a infection and (2) assess the impact of interferon (IFN)-α/ribavirin on T cell immunity.DesignT cell responses in chronic and resolved HCV genotype-3a were analysed in comparison with genotype-1 infection (total n=85) using specific peptide panels in IFN-γ ELISpot assays. T cell responses were followed longitudinally in a subset of genotype-3a infected patients receiving therapy. Responses were further defined by CD4 and CD8 subset analysis, sequencing of autologous virus and cross-reactivity of genotype-3a with genotype-1a/-1b antigens.ResultsCD8 T cell responses commonly targeted the non-structural (NS) proteins in chronic genotype-3a infection whereas in genotype-1 infection CD4 responses targeting HCV core predominated (p=0.0183). Resolved infection was associated with CD4 T cells targeting NS proteins. Paradoxically, a sustained response to therapy was associated with a brisk decline in virus-specific and total lymphocyte counts that recovered after treatment.ConclusionHCV genotype-3a exhibits a distinct T cell specificity with implications for vaccine design. However, our data do not support the theory that genotype-3a viral clearance with therapy is associated with an enhanced antiviral T cell response. Paradoxically, a reduction in these responses may serve as a biomarker of IFN responsiveness.

Chronic hepatitis C viral infection subverts vaccine‐induced T‐cell immunity in humans

“…D). A transient depletion of T cells specific for CMV, influenza, and Epstein‐Barr virus after PEG‐IFN‐α/RIB therapy has been described; however, a clear effect of treatment on antiviral T‐cell responses was not observed in this study (http://onlinelibrary.wiley.com/doi/10.1002/hep.28294/suppinfo).…”

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

“…23 Compared to the large number of studies that addressed HCV-specific CD8 + T-cell responses in HCV genotype 1 infection, only few studies have analysed HCV-specific CD8 + T-cell responses in HCV genotype 3 infection. [13][14][15] Importantly, these studies showed little cross-reactivity between peptides derived from HCV genotype 1 and 3, respectively, 13 and demonstrated that HCV genotype 3-specific CD8 + T-cell epitopes displayed minimal overlap with epitopes described for HCV genotype 1. 15 16 and HCV genotype 7 has only been described in one patient so far.…”

“…The second most common HCV genotype is genotype 3 with a proportion of up to 30% in Europe and a regional dominance in India, where this genotype most likely originates from . Compared to the large number of studies that addressed HCV‐specific CD8 + T‐cell responses in HCV genotype 1 infection, only few studies have analysed HCV‐specific CD8 + T‐cell responses in HCV genotype 3 infection . Importantly, these studies showed little cross‐reactivity between peptides derived from HCV genotype 1 and 3, respectively, and demonstrated that HCV genotype 3‐specific CD8 + T‐cell epitopes displayed minimal overlap with epitopes described for HCV genotype 1 .…”

“…To date, studies on HCV-specific CD8 + T-cell responses have been mostly limited to the HCV genotype 1, with only few studies analysing CD8 + T-cell responses targeting HCV genotypes 2 [10][11][12] or 3. [13][14][15] While HCV genotypes 1 and 3 are common in Europe and North America, and genotype 2 is common in some regions of Asia, such as Japan, HCV genotype 4 is the most common HCV genotype in many African countries. 16 As displayed in Figure 1, HCV genotype 4 is indeed common in many countries with a high prevalence of HCV infection.…”

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

“…Importantly, these 90 HCV-specific CD8+ T-cell epitopes are restricted by 25 different HLA class I alleles, including 10 HLA-A, 14 HLA-B alleles and only 1 HLA-C allele. The large majority of these epitopes were described in HCV genotype 1-infected patients, and only few studies addressed, for example, HCV genotype 3-specific CD8+ T-cell responses [20][21][22] . Compared to HCV, only few ( table 2 ).…”