Introduction The significant rise in incidence of Hepatitis C virus (HCV) infection among men‐who‐have‐sex‐with‐men (MSM) living with HIV‐1 suggests that HCV under specific circumstances is transmitted via sexual contact. During sexual transmission HCV has to cross the epithelial barrier to either directly enter the blood stream or indirectly via mucosal immune cells. However, the mechanisms of sexual transmission of HCV remain unclear. We investigated the role of Langerhans cells (LCs) in HCV susceptibility during sexual contact as LCs are among the first cells in mucosal tissues to encounter invading viruses. Methods We investigated the phenotype of primary LCs in anal biopsies from MSM living with HIV‐1. To investigate the role of primary LCs in HCV infection and transmission, we have used both isolated primary skin LCs and the ex vivo tissue transmission model. Results Our data identified an important role for mucosal LCs in facilitating HCV transmission after HIV‐1 exposure or immune activation. LCs were detected within mucosal anal tissues obtained from HIV‐1 positive MSM biopsies. In order to perform functional studies, we used primary LCs from skin, which have a similar phenotype as mucosal LCs. Immature LCs were neither infected nor transmitted HCV to hepatocytes. Notably, exposure to HIV‐1 significantly increased HCV transmission by LCs in the ex vivo transmission model. HIV‐1 replication was crucial for the increased HCV transmission as HIV‐1 inhibitors significantly reduced HIV‐1‐induced HCV transmission. Moreover, tissue immune activation of LCs also increased HCV transmission to target cells. Conclusions Thus, our data strongly indicate that HIV‐1 or immune activation in MSM leads to capture of HCV by mucosal LCs, which might facilitate transmission to other cells or allow entry of HCV into the blood. This novel transmission mechanism by LCs also implicates that the activation state of LCs is an important cellular determinant for HCV susceptibility after sexual contact.

Background & Aims Despite high‐risk behaviour, 10%‐20% of HCV multiple exposed individuals remain uninfected (MEU), whilst the remainder become infected (MEI). We hypothesize that host factors play a role in HCV susceptibility. We aimed to identify polymorphisms in host genes that encode for proteins involved in viral entry: CD81, Scavenger receptor 1 (SR‐1), Low‐density lipoprotein receptor (LDL‐R), Claudin‐1 (CLDN1), Occludin (OCLN) and Niemann‐Pick C1–like 1 (NPC1L1). Methods Multiple exposed infected and MEU from two observational cohorts were selected. From the MSM study of acute infection with HCV (MOSAIC), HIV‐1 infected MEU cases (n = 30) and HIV‐1 infected MEI controls (n = 32) were selected based on reported high‐risk behaviour. From the Amsterdam Cohorts Studies (ACS) injecting drug users (IDU) cohort, MEU cases (n = 40) and MEI controls (n = 22) were selected who injected drugs for ≥2 years, in the nineties, when HCV incidence was high. Selected single nucleotide polymorphisms (SNPs) were determined by sequencing or SNP assays. Results No associations were found for SNPs within genes coding for CD81, SR‐1, Claudin‐1 or Occludin between the MEU and MEI individuals from either cohort. We did observe a significant association for rs688 within the LDL‐R gene with HCV infection (OR: 0.41 P = 0.001), however, LDL cholesterol levels did not vary between individuals carrying the differential SNPs. Additionally, a marginal significant effect was found for rs217434 and rs2072183 (OR: 2.07 P = 0.032 and OR: 1.76 P = 0.039, respectively) within NPC1L1. Conclusions Our results demonstrate that the rs688 SNP within the LDL‐R gene associates with HCV susceptibility through mucosal as well as intravenous exposure.