HIV-1 exposure and immune activation enhance sexual transmission of Hepatitis C virus by primary Langerhans cells.

Bernadien M Nijmeijer,Carla Ms Ribeiro,Ramin Sarrami‐Forooshani,Renée Rce Schreurs,Sylvie M Koekkoek,Matthijs L Siegenbeek Van Heukelom,Gaby S Steba,Peter Reiss,Marc Valk,Richard Molenkamp,Teunis Bh Geijtenbeek,Janke Schinkel

doi:10.1002/jia2.25268

Bernadien M Nijmeijer, Carla Ms Ribeiro + Show 10 more

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https://doi.org/10.1002/jia2.25268

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Abstract

IntroductionThe 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.MethodsWe 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.ResultsOur 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.ConclusionsThus, 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.

Highlights

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
Treatment with directly acting antivirals (DAA) against HCV is very effective in clearing HCV [14], MSM living with HIV-1 remain at high risk of reinfection [4,15,16]
We identified mucosal Langerhans cells (LCs) in anal biopsies from MSM living with HIV-1

Summary

| INTRODUCTION

115 million people are infected with Hepatitis C virus (HCV) whereas 37 million people are infected with HIV1, and approximately two million infected with both HIV-1 and HCV [1]. Treatment with directly acting antivirals (DAA) against HCV is very effective in clearing HCV [14], MSM living with HIV-1 remain at high risk of reinfection [4,15,16] These recent studies suggest that HCV is sexually transmitted within MSM [17], whereas sexual transmission of HCV within heterosexual HIV-1 infected or uninfected individuals is rare [18]. It has been shown that HCV is shed into the rectum in HIV-1 positive men with HCV infection [21] These studies strongly suggest that the rectal mucosa is the primary entry site for HCV entry in MSM after sexual contact, and that unknown mechanisms allow changes within the mucosa that increase susceptibility to HCV.

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