Abstract
Sexually transmitted Hepatitis C virus (HCV) infections and high reinfections are a major concern amongst men who have sex with men (MSM) living with HIV-1 and HIV-negative MSM. Immune activation and/or HIV-1 coinfection enhance HCV susceptibility via sexual contact, suggesting that changes in immune cells or external factors are involved in increased susceptibility. Activation of anal mucosal Langerhans cells (LCs) has been implicated in increased HCV susceptibility as activated but not immature LCs efficiently retain and transmit HCV to other cells. However, the underlying molecular mechanism of transmission remains unclear. Here we identified the Heparan Sulfate Proteoglycan Syndecan 4 as the molecular switch, controlling HCV transmission by LCs. Syndecan 4 was highly upregulated upon activation of LCs and interference with Heparan Sulfate Proteoglycans or silencing of Syndecan 4 abrogated HCV transmission. These data strongly suggest that Syndecan 4 mediates HCV transmission by activated LCs. Notably, our data also identified the C-type lectin receptor langerin as a restriction factor for HCV infection and transmission. Langerin expression abrogated HCV infection in HCV permissive cells, whereas langerin expression on the Syndecan 4 expressing cell line strongly decreased HCV transmission to a target hepatoma cell line. These data suggest that the balanced interplay between langerin restriction and Syndecan 4 transmission determines HCV dissemination. Silencing of langerin enhanced HCV transmission whereas silencing Syndecan 4 on activated LCs decreased transmission. Blocking Heparan Sulfate Proteoglycans abrogated HCV transmission by LCs ex vivo identifying Heparan Sulfate Proteoglycans and Syndecan 4 as potential targets to prevent sexual transmission of HCV. Thus, our data strongly suggest that the interplay between receptors promotes or restricts transmission and further indicate that Syndecan 4 is the molecular switch controlling HCV susceptibility after sexual contact.
Highlights
Viral hepatitis is responsible for an estimated 1.3 million deaths from acute infection, hepatitis-related liver cancer and cirrhosis in 2015 [1]
As HSPGs are known receptors for Hepatitis C virus (HCV) on hepatocytes [36, 37] we investigated the role of heparan sulfates in Langerhans cells (LCs)-mediated HCV transmission
Acquired Hepatitis C virus predominantly occurs amongst men who have sex with men (MSM) living with human immunodeficiency virus type 1 (HIV-1) [2,3,4,5,6,7,8,9] and increasing cases of sexually acquired HCV have been reported amongst HIV-1 negative MSM eligible for or on preexposure prophylaxis (PrEP) [15,16,17, 47,48,49]
Summary
Viral hepatitis is responsible for an estimated 1.3 million deaths from acute infection, hepatitis-related liver cancer and cirrhosis in 2015 [1]. As new HCV infections were typically found in MSM living with human immunodeficiency virus type 1 (HIV-1), it was suggested that the HIV-1 status is an important risk factor for sexually acquired HCV [8, 9, 11, 14]. Potential mechanisms for increased rates of sexual transmission of HCV among MSM may include high-risk practices [4] and unprotected mucosal traumatic sex leading to rectal bleeding [18] which could lead to disruption of the mucosal integrity allowing HCV to cross the epithelial barrier to either directly enter the blood stream or indirectly via immune cells promoting sexual transmission of HCV. We have previously shown an important role for Langerhans cells (LCs) in HCV transmission during HIV-1 coinfection and upon immune activation [19]
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