Effects of the CCR5-Δ32 Mutation on Hepatitis C Virus-Specific Immune Responses in Patients with Haemophilia

Abstract

In hepatitis C virus (HCV) infection antiviral T cells express the CC chemokine receptor 5 (CCR5). Their recruitment to the liver is an important step in the immune response. A 32 base pair deletion in the CCR5 gene leads to reduced expression and total loss of CCR5 in CCR5-Delta32 heterozygous and homozygous subjects, respectively. However, the role of this mutation for antiviral immunity remains unclear. Here, we analysed proliferation, IFN-gamma and IL-4 secretion (ELISpot) induced by the HCV antigens core, NS3, NS4, and NS5a in 21 anti-HCV-positive haemophiliac patients in relationship to their CCR5 genotypes (CCR5 wildtype n = 10, CCR5-Delta32 heterozygous n = 5 and CCR5-Delta32 homozygous n = 6). Furthermore, T cell migration in response to the CCR5 ligands CCL3, -4 and -5 was studied. Overall IFN-gamma responses to HCV proteins were only slightly greater in CCR5 wild-type patients than in CCR5-Delta32 carriers (0.6 versus 0.24 SFC/10(4) PBMC; p = 0.043). This difference was consistently seen with all tested HCV antigens. In contrast, neither T cell migration, nor PBMC proliferation, nor IL-4 production differed between CCR5 genotypes. Interruption of the CCR5 signalling pathway due to CCR5-Delta32 may potentially result in subtle reduction of HCV specific IFN-gamma responses in anti-HCV-positive haemophiliac patients.

CCR5 receptor antagonism inhibits hepatitis C virus (HCV) replication in vitro

“…[8] However, HCV-specific immune responses may be impaired by the CCR5 delta-32 mutation as well. [9] Wald et al . suggested that the CCR5 delta-32 allele may be associated with decreased hepatic inflammation in HCV-infected patients using histopathologic outcome measures.…”

The predictive value of IL28B gene polymorphism for spontaneous clearance in a single source outbreak cohort is limited in patients carrying the CCR5Δ32 mutation

“…Accordingly, mice lacking CCR5 showed impaired macrophage function and reduced efficiency to clear Listeria monozytogenes infection [51]. However, in humans, immune dysfunction associated with the CCR5D32 mutation is rather subtle in T lymphocytes but seems to involve HCV-specific interferon-gamma production [52]. Beyond that, the CCR5 receptor is critically involved in hepatic recruitment of immuno-competent cells, including dendritic cells (DC).…”

Effects of the Chemokine Receptor 5 (CCR5)-Delta32 Mutation on Hepatitis C Virus-Specific Immune Responses and Liver Tissue Pathology in HCV Infected Patients

“…Chemokines and chemokine receptors have been shown to be critically involved in these processes (20) and CCR5Δ32 bpdel carriers of HCV positive patients (as presented in the current study) remain poor clearance during the HCV therapy by the masking of some other related genotypes (20, 21). Ahlenstiel et al have claimed that point mutation in CCR5-Delta32 interrupts the CCR5 signalling pathway due to may potentially result in subtle reduction of HCV specific IFN-gamma responses in anti-HCV-positive haemophiliac patients (22). The current limited results and some other recent literature findings support the above hypotheses (23-26).…”