Impaired hepatitis C virus (HCV)-specific interferon-γ responses in individuals with HIV who acquire HCV infection: correlation with CD4(+) T-cell counts

Abstract

Studies examining the effect of coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) on the HCV-specific immune response in acute HCV infection are limited. This study directly compared acute HCV-specific T-cell responses and cytokine profiles between 20 HIV/HCV-coinfected and 20 HCV-monoinfected subjects, enrolled in the Australian Trial in Acute Hepatitis C (ATAHC), using HCV peptide enzyme-linked immunospot (ELISPOT) and multiplex in vitro cytokine production assays. HIV/HCV coinfection had a detrimental effect on the HCV-specific cytokine production in acute HCV infection, particularly on HCV-specific interferon γ (IFN-γ) production (magnitude P = .004; breadth P = .046), which correlated with peripheral CD4(+) T-cell counts (ρ = 0.605; P = .005) but not with detectable HIV viremia (ρ = 0.152; P = .534).

Figure 1.

Magnitude and breadth of HCV-specific interferon γ (IFN-g) and interleukin 2 (IL-2) enzyme-linked immunospot (ELISPOT) assay responses to 10 HCV peptide pools (core, E1, E2, p7, NS2, NS3, NS4a, NS4b, NS5a, and NS5b) from the screening time point in subjects coinfected with human immunodeficiency virus (HIV) and HCV (n = 20) or monoinfected with HCV (n = 20). A, HIV/HCV-coinfected subjects had significantly fewer HCV-specific IFN-γ–producing cells at screening (black squares) than HCV-monoinfected subjects (black triangles) (range, 0–350 vs 0–800 summed spot-forming cells [SFCs]/10⁶ peripheral blood mononuclear cells [PBMCs], respectively; Mann–Whitney test, P = .042, ). B, HIV/HCV-coinfected subjects also had a significantly lower breadth of HCV-specific IFN-γ responses at screening than HCV-monoinfected subjects (median, 0 vs 1 pool positive, respectively; P = .046). C, HIV/HCV-coinfected subjects had lower HCV-specific IL-2 responses at screening than HCV-monoinfected subjects (range, 0–210 vs 0–370 summed SFCs/10⁶ PBMCs, respectively; P = 0.294). D, The breadth of IL-2 responses was similar in the 2 cohorts (median, 0 pools positive for both; P = .383). For A–D, each square or triangle represents an individual subject's response, and the horizontal black lines represent median responses; *P < .05. E, Correlation of HCV-specific IFN-γ cytokine production with CD4⁺ T-cell counts in HIV/HCV-coinfected subjects from the ELISPOT assay at screening. High-magnitude IFN-γ production was significantly correlated with CD4⁺ T-cell counts (Spearman correlation ρ = 0.61; P = .005). F, A similar trend was seen for broad IFN-γ responses associated with higher CD4⁺ T-cell counts (ρ = 0.40 P = .084). G, HCV-specific IFN-γ cytokine production from the ELISPOT assay at screening also correlated with nadir CD4⁺ T-cell counts in HIV/HCV-coinfected subjects (Spearman correlation for IFN-γ magnitude, ρ = 0.52 P = .020). H, IFN-γ responses to non-HCV antigens, gytomegalovirus, Epstein-Barr virus, and flu virus peptides were significantly higher in coinfected subjects than in monoinfected subjects (range, 0–2000 vs 0–420 SFCs/10⁶ PBMCs, respectively; Mann-Whitney test, P = .022, ). *P < .05 I, Distribution of HCV genotype between cohorts. There was no significance difference in the distribution of genotypes between the cohorts (Fisher exact test, P = .285), nor between the number of genotype 1 subjects in each cohort (Fisher exact test, P = .100). J, Although the HIV/HCV-coinfected cohort included more genotype 1 subjects, the magnitude of IFN-γ responses was lower in this cohort. There was no significant difference in HCV-specific cytokine production between genotype 1 and non–genotype 1 subjects in either cohort (P > .500).

Figure 1.

Magnitude and breadth of HCV-specific interferon γ (IFN-g) and interleukin 2 (IL-2) enzyme-linked immunospot (ELISPOT) assay responses to 10 HCV peptide pools (core, E1, E2, p7, NS2, NS3, NS4a, NS4b, NS5a, and NS5b) from the screening time point in subjects coinfected with human immunodeficiency virus (HIV) and HCV (n = 20) or monoinfected with HCV (n = 20). A, HIV/HCV-coinfected subjects had significantly fewer HCV-specific IFN-γ–producing cells at screening (black squares) than HCV-monoinfected subjects (black triangles) (range, 0–350 vs 0–800 summed spot-forming cells [SFCs]/10⁶ peripheral blood mononuclear cells [PBMCs], respectively; Mann–Whitney test, P = .042, ). B, HIV/HCV-coinfected subjects also had a significantly lower breadth of HCV-specific IFN-γ responses at screening than HCV-monoinfected subjects (median, 0 vs 1 pool positive, respectively; P = .046). C, HIV/HCV-coinfected subjects had lower HCV-specific IL-2 responses at screening than HCV-monoinfected subjects (range, 0–210 vs 0–370 summed SFCs/10⁶ PBMCs, respectively; P = 0.294). D, The breadth of IL-2 responses was similar in the 2 cohorts (median, 0 pools positive for both; P = .383). For A–D, each square or triangle represents an individual subject's response, and the horizontal black lines represent median responses; *P < .05. E, Correlation of HCV-specific IFN-γ cytokine production with CD4⁺ T-cell counts in HIV/HCV-coinfected subjects from the ELISPOT assay at screening. High-magnitude IFN-γ production was significantly correlated with CD4⁺ T-cell counts (Spearman correlation ρ = 0.61; P = .005). F, A similar trend was seen for broad IFN-γ responses associated with higher CD4⁺ T-cell counts (ρ = 0.40 P = .084). G, HCV-specific IFN-γ cytokine production from the ELISPOT assay at screening also correlated with nadir CD4⁺ T-cell counts in HIV/HCV-coinfected subjects (Spearman correlation for IFN-γ magnitude, ρ = 0.52 P = .020). H, IFN-γ responses to non-HCV antigens, gytomegalovirus, Epstein-Barr virus, and flu virus peptides were significantly higher in coinfected subjects than in monoinfected subjects (range, 0–2000 vs 0–420 SFCs/10⁶ PBMCs, respectively; Mann-Whitney test, P = .022, ). *P < .05 I, Distribution of HCV genotype between cohorts. There was no significance difference in the distribution of genotypes between the cohorts (Fisher exact test, P = .285), nor between the number of genotype 1 subjects in each cohort (Fisher exact test, P = .100). J, Although the HIV/HCV-coinfected cohort included more genotype 1 subjects, the magnitude of IFN-γ responses was lower in this cohort. There was no significant difference in HCV-specific cytokine production between genotype 1 and non–genotype 1 subjects in either cohort (P > .500).