HLA-Bw4 80(T) and multiple HLA-Bw4 copies combined with KIR3DL1 associate with spontaneous clearance of HCV infection in people who inject drugs

- KIR3DL1/HLA-Bw4 80(T) associates with spontaneous clearance of HCV in PWID.
- Multiple HLA-Bw4 alleles associate with an anti-HCV seronegative state in PWID.
- KIR3DL1+ NK cells from HLA-Bw4 80(T)-positive PWID show superior functionality.
- HLA-Bw4 copy number correlates with functionality of KIR3DL1+ NK cells.
- Distinct mechanisms mediated by KIR3DL1-ligands protect against chronic HCV in PWID

Background & AimsNatural killer (NK) cell function is regulated by inhibitory and activating receptors including killer cell immunoglobulin-like receptors (KIRs). Here, we analyzed the impact of different KIR/KIR-ligand genotypes on the outcome of hepatitis C virus (HCV) infection in people who inject drugs (PWID).MethodsKIR/KIR-ligand genotypes associated with spontaneous clearance of HCV infection were identified in a cohort of PWID from Germany (n = 266) and further validated in a second anti-HCV positive cohort of PWID recruited in North America (n = 342). NK cells of PWID and healthy donors were functionally characterized according to their KIR/KIR-ligand genotype by flow cytometry.ResultsMultivariate logistic regression analysis revealed that KIR3DL1/HLA-Bw4 80(T) was associated with spontaneous clearance of HCV infection in PWID, which was confirmed in the PWID cohort from North America. Compared with PWID with detectable HCV RNA, the frequency of individuals with multiple HLA-Bw4 alleles was significantly higher in anti-HCV positive PWID with resolved HCV infection (29.7% vs. 15.2%; p = 0.0229) and in anti-HCV seronegative PWID (39.2%; p = 0.0006). KIR3DL1+ NK cells from HLA-Bw4 80(T)-positive PWID showed superior functionality compared to HLA-Bw4 80(I)-positive PWID. This differential impact was not observed in healthy donors; however, the HLA-Bw4 copy number strongly correlated with the functionality of KIR3DL1+ NK cells.ConclusionsHLA-Bw4-80(T) and multiple HLA-Bw4 copies in combination with KIR3DL1 are associated with protection against chronic hepatitis C in PWID by distinct mechanisms. Better licensing of KIR3DL1+ NK cells in the presence of multiple HLA-Bw4 copies is beneficial prior to seroconversion whereas HLA-Bw4 80(T) may be beneficial during acute hepatitis C.Lay summary: Natural killer (NK) cells are part of the innate immune system and are regulated by a complex network of activating and inhibiting receptors. The regulating receptor-ligand pairs of an individual are genetically determined. Here, we identified a particular set of ligand and receptor genes that are associated with better functionality of NK cells and better outcome upon exposure to HCV in a high-risk group.

After exposure to HCV, the majority of PWID develop chronic HCV infection that can lead to liver cirrhosis and hepatocellular carcinoma. A small subgroup of PWID is able to clear HCV infection before and after seroconversion. PWID with multiple Bw4 alleles are more likely to clear HCV prior to seroconversion than PWID with one or no Bw4 allele. In addition, PWID that encode both KIR3DL1 and a Bw4 80(T) motif have higher chances of spontaneously clearing HCV after seroconversion.143