HCV‐specific T‐cell responses in injecting drug users: evidence for previous exposure to HCV and a role for CD4+ T cells focussing on nonstructural proteins in viral clearance

Abstract

SUMMARY. In order to understand the parameters associated with resolved hepatitis C virus (HCV)-infection, we analysed the HCV-specific T-cell responses longitudinally in 13 injecting drug-users (IDUs) with a prospectively identified acute HCV infection. Seven IDUs cleared HCV and six IDUs remained chronically infected. T-cell responses were followed in the period needed to resolve and a comparable time span in chronic carriers. Ex vivo T-cell responses were measured using interferon-c Elispot assays after stimulation with overlapping peptide pools spanning the complete HCV genome. CD4+ memory-T-cell responses were determined after 12-day stimulation with HCV proteins. The maximum response was compared between individuals. The T-cell responses measured directly ex vivo were weak but significantly higher in resolvers compared to chronic carriers, whereas the CD4+ memory-T-cell response was not different between resolvers and chronic carriers. However, HCV Core protein was targeted more often in chronic carriers compared to individuals resolving HCV infection. CD4+ T-cell responses predominantly targeting nonstructural proteins were associated with resolved HCV infection. Interestingly, observation of memory-T-cell responses present before the documented HCV-seroconversion suggests that reinfections in IDUs occur often. The presence of these responses however, were not predictive for the outcome of infection. However, a transition of the HCV-specific CD4+ memory-Tcell response from targeting Core to targeting nonstructural proteins during onset of infection was associated with a favourable outcome. Therefore, the specificity of the CD4+ memory-T-cell responses measured after 12-day expansion seems most predictive of resolved infection.

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

“…These responses appear to be largely from CD4 ϩ T cells, according to a number of previous analyses that include depletion studies [16,24], CFSE proliferation [27], and cytokine-based flow assays [16] In contrast, previous detailed mapping studies of CD8 ϩ T cell responses in HCVpositive donors failed to reveal ex vivo responses targeting HCV core [7]. Similar data concerning CD4 ϩ T cell responses targeting core in chronic infection have been obtained by other investigators [26]. Analysis of core peptide-specific responses is not a comprehensive analysis but provides a target population of T cells present before treatment to track over time.…”

“…Before therapy, HCV core-specific T cell responses, which we and others have shown previously to comprise largely CD4 ϩ T cells [7,16,26,27], were detected in 21 of 31 patients, including 10 of 15 patients in the SVR group and 11 of 16 patients in the non-SVR group ( figure 1A). The mean viral load, ALT level, and HCV core-specific responses detected by IFN-␥ ELISpot assay were lower in patients who achieved an SVR than in those in the non-SVR group (mean Ϯ SD viral load, 5.791 Ϯ 0.1723 vs. 5.990 Ϯ 0.1181 log 10 IU/mL; ALT level, 118.4 Ϯ 27.25 vs. 134.9 Ϯ 29.44 IU/L; core response, 85.07 Ϯ 31.58 vs. 187.9 Ϯ 94.09 sfu/1 ϫ 10 6 PBMCs), although these differences did not reach statistical significance.…”

Female Sex and IL28B, a Synergism for Spontaneous Viral Clearance in Hepatitis C Virus (HCV) Seroconverters from a Community-Based Cohort

“…As in line with our findings that early HIV infection already lowers the HCV clearance rate. We and others have shown that acute HIV co-infection hampers the beneficial HCV-specific CD4 + T-cell responses targeting non-structural proteins in DU [33]–[37].…”

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

“…The ‘equivalent’ genotype-1a peptide, which differs by two amino acids, is known to be a DRB1 1101 restricted CD4 T cell target 31. In contrast, in genotype-1 infection, CD4 T cells are known to target a broad range of epitopes within core 23 24 34. Viral sequence analysis in 4/5 patients showed no evidence of viral escape supporting previous data in humans,23 and chimpanzees,35 showing that CD4 T cells unlike CD8 T cells rarely exert selection pressure on HCV.…”