Cellular Immune Responses during High‐Dose Interferon‐α Induction Therapy for Hepatitis C Virus Infection

Barnes, Eleanor; Gelderblom, Huub C.; Humphreys, Isla; Semmo, Nasser; Reesink, H. W.; Beld, Marcel; Lier, R. A. W. Van; Klenerman, Paul

doi:10.1086/597072

Cited by 41 publications

(34 citation statements)

References 28 publications

(51 reference statements)

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“…However, studies on HCV dynamics typically include a small number of patients. 11,21,27,30,33,34,37,[39][40][41][42][52][53][54][55][56][57][58] Despite this limitation, we identified a delayed early HCV kinetics pattern in LT patients that should be further investigated in larger studies before drawing any definitive conclusion.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C virus viral kinetics during α-2a or α-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes

Berenguer

Ortíz-Cantó

Abellán

et al. 2012

Journal of Clinical Virology

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Section: Discussionmentioning

confidence: 99%

Hepatitis C virus viral kinetics during α-2a or α-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes

Berenguer

Ortíz-Cantó

Abellán

et al. 2012

Journal of Clinical Virology

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“…Frozen PBMC enabled the concurrent assessment of T cell responses sampled at different time points. Thawed PBMC were tested by IFN-γ (Mabtech, Nacka Strand, Sweden) ELISpot assays, as previously described 20. Briefly, viable PBMC (200 000/well) plated in duplicate were stimulated for 18 h with peptide pools A-M (3 μg/ml), cytomegalovirus (CMV) lysate (0.05 μg/ml, Chiron), influenza, Epstein-Barr virus (EBV) and CMV (FEC) CD8 epitopes in a single pool (3 μg/ml BEI resources).…”

Section: Methodsmentioning

confidence: 99%

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

Humphreys

Delft

Brown

et al. 2012

Gut

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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.

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“…The same holds true for human persistent infections with the exception of IFNα-based therapies for chronic viral hepatitis. IFNα has a known immunomodulatory effect during therapy, rendering studies of immune function difficult to interpret2930. The fate of exhausted virus-specific CD8 + T cells after removal of persistent antigen, however, is of central clinical relevance since it has implications for protection from re-infection after antigen elimination.…”

mentioning

confidence: 99%

TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation

et al. 2017

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Differentiation and fate of virus-specific CD8+ T cells after cessation of chronic antigen stimulation is unclear. Here we show that a TCF1+CD127+PD1+ hepatitis C virus (HCV)-specific CD8+ T-cell subset exists in chronically infected patients with phenotypic features of T-cell exhaustion and memory, both before and after treatment with direct acting antiviral (DAA) agents. This subset is maintained during, and for a long duration after, HCV elimination. After antigen re-challenge the less differentiated TCF1+CD127+PD1+ population expands, which is accompanied by emergence of terminally exhausted TCF1-CD127-PD1hi HCV-specific CD8+ T cells. These results suggest the TCF1+CD127+PD1+ HCV-specific CD8+ T-cell subset has memory-like characteristics, including antigen-independent survival and recall proliferation. We thus provide evidence for the establishment of memory-like virus-specific CD8+ T cells in a clinically relevant setting of chronic viral infection and we uncover their fate after cessation of chronic antigen stimulation, implicating a potential strategy for antiviral immunotherapy.

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Cellular Immune Responses during High‐Dose Interferon‐α Induction Therapy for Hepatitis C Virus Infection

Abstract: High-dose IFN-alpha induction therapy leads to a profound decline in IL-2- and IFN-gamma-secreting HCV- and CMV-specific T cells. These data indicate that restoration of T cell responses is unlikely to be causally linked to an early response or SVR to therapy.

Cited by 41 publications

References 28 publications

Hepatitis C virus viral kinetics during α-2a or α-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes

Hepatitis C virus viral kinetics during α-2a or α-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes

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

TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation

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