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. 1999 Mar;44(3):424–429. doi: 10.1136/gut.44.3.424

Hepatitis C virus (HCV) specific immune responses in anti-HCV positive patients without hepatitis C viraemia

M Cramp 1, P Carucci 1, S Rossol 1, S Chokshi 1, G Maertens 1, R Williams 1, N Naoumov 1
PMCID: PMC1727419  PMID: 10026332

Abstract

BACKGROUND/AIMS—Most patients infected with hepatitis C virus (HCV) develop chronic infection and persistent viraemia. The immune mechanisms responsible for resolution of viraemia remain poorly understood. HCV specific humoral and cellular immune responses in patients with and without viraemia were investigated. 
METHODS—In vitro T helper (TH) lymphocyte responses to structural and non-structural HCV proteins were determined by means of proliferative response and cytokine production in 35 anti-HCV positive/HCV RNA negative patients and in 31 patients with chronic HCV infection and persistent viraemia. Humoral responses were determined by measuring HCV specific antibody quantity and specificity. 
RESULTS—A TH response to two or more HCV proteins was present in 18 of 35 patients with serological viral clearance compared with just one of 31 viraemic patients (p = 0.00001). HCV specific interferon-γ production was increased only in the former group. In contrast, the antibody levels were significantly lower and directed at fewer HCV antigens in patients with undetectable HCV RNA. 
CONCLUSIONS—Patients without viraemia after HCV infection frequently have strong TH lymphocyte responses of the TH1 type to multiple HCV antigens many years after the onset of infection, whereas antibody responses are less marked. These results suggest that control of HCV replication may depend on effective TH lymphocyte activation. 



Keywords: hepatitis C virus; liver; Th1/Th2 cells; T helper cytokines; viral clearance

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Figure 1 .

Figure 1

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Presence of significant TH cell proliferative response to hepatitis C virus (HCV) antigens in patients with viral clearance (group A) compared with that in patients with viral persistence (group B). (A) Percentage of patients in groups A and B with a significant response to two or more HCV proteins. Numbers above bars are numbers responding/numbers tested. p value was calculated using the χ2 test. (B) Number of patients in each group with a significant response to various numbers of HCV proteins. 


Figure 2 .

Figure 2

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Effect of CD4 cell depletion on response to hepatitis C virus (HCV) non-structural protein 4 (NS4); confirmation that the proliferative response to HCV antigens is restricted to CD4 lymphocytes. Progressive depletion of CD4 lymphocytes from the pool of peripheral blood mononuclear cells progressively reduces the stimulation index (SI) to NS4 in a typical case. 


Figure 3 .

Figure 3

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Comparison of in vitro production of interferon-γ (A) and interleukin-10 (B) in response to hepatitis C virus (HCV) proteins in patients with viral clearance (group A) and patients with viral persistence (group B). Bars indicate mean concentration of cytokine produced by lymphocytes cultured in the absence of HCV proteins (no anitgen) or in the presence of HCV proteins (with antigen). Vertical lines represent standard error. p values were calculated using the Wilcoxon test on all values. 


Figure 4 .

Figure 4

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Comparison between groups A (shaded bars) and B (solid bars) of antibody responses to individual hepatitis C virus (HCV) antigens as measured by LIA-Scan. (A) The percentage of patients with detectable antibody to each HCV antigen. p values were calculated using the χ2 test. (B) Quantification of serum antibody levels in arbitrary units to HCV non-structural protein (NS)3, NS4, NS5, core 1, core 2, and E2. Bars represent mean values from all those with detectable antibody, excluding values of zero or below the cut off value. Vertical lines represent standard error. p values were calculated using the Mann-Whitney U test for unpaired samples. Core 1 and core 2 are non-overlapping epitope clusters from HCV core. E2 refers to envelope 2/hypervariable region 1. 


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