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-n32 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-n32 heterozygous n = 5 and CCR5-n32 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-n32 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-n32 may potentially result in subtle reduction of HCV specific IFN-gamma responses in anti-HCV-positive haemophiliac patients.

Beyond HIV infection: Neglected and varied impacts of CCR5 and CCR5Δ32 on viral diseases

“…In the context of persistence/resolution of HCV infection and viral control, in the one hand, studies described association of the CCR5Δ32 allele with reduced rates of spontaneous viral clearance (Nattermann et al, 2011;Morard et al, 2014), higher viral load (Yilmaz et al, 2014), and reduced anti−HCV immune response (Ahlenstiel et al, 2009). On the other hand, studies have reported association between the CCR5Δ32 variant and increased rates of spontaneous viral clearance (Goulding et al, 2005;El-Moamly et al, 2013).…”

The role of CCR5 in HCV infection

“…Moreover, Ahlenstiehl et al could show a significantly decreased HCV-specific IFN-γ response of CD8(+) T-cells in carriers of the CCR5Δ32 allele as compared to cells from patients with a homozygeous wildtype genotype. This finding suggests the CCR5Δ32 polymorphisms to possibly affect cellular immune responses in HCV infection [43]. …”

Role of Host Genetic Factors in the Outcome of Hepatitis C Virus Infection

“…However, no association of different CCR5 gene alleles with viral persistence was found in several other cohorts [104, 109, 111, 112]. A recent study addressed the effects of CCR5delta32 mutation on HCV specific T cell responses [113]. IFN-γ responses were reduced in patients carrying the mutation but other T cell functions (migration, proliferation, IL-4 production) were not altered.…”