Abstract Body

Sexual transmission of Hepatitis C virus (HCV), until recently, was thought to be rare. However, there has been a significant rise in the incidence of HCV infection among HIV-infected men-who-have-sex-with-men (MSM) and studies suggest that HCV can be sexually transmitted within this population. The mechanisms underlying this sexual transmission are unclear. Human Langerhans cells (LCs) have been shown to be involved in limiting dissemination upon sexual contact by degrading HIV-1 and preventing HIV-1 transmission. The activation state of LCs changes susceptibility to HIV-1, leading to LC infection and subsequent HIV-1 transmission. In this study we investigated the role of LCs in HCV infection and transmission. We hypothesized that HIV-1 replication in HIV-1-infected MSM leads to mucosal changes that allow HCV entry and subsequent dissemination to hepatocytes.

Therefore, we analyzed the immune cells within mucosal anal biopsies from HIV-1 infected MSM individuals as a potential entry route for HCV during sexual contact. We investigated the role of LCs in HCV infection and transmission using human primary isolated LCs and the ex vivo tissue transmission model.

Notably, we detected Langerhans cells (LCs) within the mucosal anal tissue. Immature LCs were neither infected nor transmitted HCV to hepatocytes in vitro and ex vivo. As sexual transmission is mostly observed within HIV-1 infected individuals, we pre-exposed tissues with HIV-1 and, strikingly, HIV-1 pre-exposure significantly increased HCV transmission by LCs. HIV-1 replication is crucial for the increased HCV transmission as treating ex vivo tissue with HIV-1 replication inhibitors significantly decreased HIV-1-induced HCV transmission. Activation of LCs did not lead to infection by HCV but these activated LCs, in contrast to immature LCs from same donor, were efficient in transmitting HCV to hepatocytes.

Thus, our data strongly suggest that HIV-1 replication in mucosal tissues in HIV-1 infected MSM changes LC function, which causes HCV capture and subsequent transmission to hepatocytes. This novel transmission mechanism by LCs implicates also that the activation state of LCs is an important determinant for HCV susceptibility after sexual contact.