Influence of HLA-C environment on the spontaneous clearance of hepatitis C in European HIV–HCV co-infected individuals

Abstract

Summary Natural killer (NK) cell functions are regulated by diverse inhibitory and activating receptors, including killer cell immunoglobulin-like receptors (KIR), which interact with human leukocyte antigen (HLA) class I molecules. Some KIR/HLA genetic combinations were reported associated with spontaneous clearance (SC) of hepatitis C virus (HCV) but with discordant results, possibly reflecting KIR and/or HLA gene polymorphism according to populations. KIR/HLA genetic combinations associated with both an exhaustive NK and T cell repertoire were investigated in a cohort of HIV–HCV co-infected individuals with either SC (n = 68) or chronic infection (CI, n = 163) compared to uninfected blood donors [controls (Ctrl), n = 100]. Multivariate analysis showed that the HLA C2C2 environment was associated with SC only in European HIV–HCV co-infected individuals [odds ratio (OR) = 4·30, 95% confidence interval = 1·57–12·25, P = 0·005]. KIR2D+ NK cell repertoire and potential of degranulation of KIR2DL1/S1+ NK cells were similar in the SC European cohort compared to uninfected individuals. In contrast, decreased frequencies of KIR2DS1+ and KIR2DL2+ NK cells were detected in the CI group of Europeans compared to SC and a decreased frequency of KIR2DL1/S1+ NK cells compared to controls. Regarding T cells, higher frequencies of DNAX accessory molecule-1 (DNAM-1)+ and CD57+ T cells were observed in SC in comparison to controls. Interestingly, SC subjects emphasized increased frequencies of KIR2DL2/L3/S2+ T cells compared to CI subjects. Our study underlines that the C2 environment may activate efficient KIR2DL1+ NK cells in a viral context and maintain a KIR2DL2/L3/S2+ mature T cell response in the absence of KIR2DL2 engagement with its cognate ligands in SC group of HCV–HIV co-infected European patients.