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Immune activation of vaginal human Langerhans cells increases susceptibility to HIV-1 infection.

ABSTRACT: Vaginal inflammation increases the risk for sexual HIV-1 transmission but underlying mechanisms remain unclear. In this study we assessed the impact of immune activation on HIV-1 susceptibility of primary human vaginal Langerhans cells (LCs). Vaginal LCs isolated from human vaginal tissue expressed a broad range of TLRs and became activated after exposure to both viral and bacterial TLR ligands. HIV-1 replication was restricted in immature vaginal LCs as only low levels of infection could be detected. Notably, activation of immature vaginal LCs by bacterial TLR ligands increased HIV-1 infection, whereas viral TLR ligands were unable to induce HIV-1 replication in vaginal LCs. Furthermore, mature vaginal LCs transmitted HIV-1 to CD4 T cells. This study emphasizes the role for vaginal LCs in protection against mucosal HIV-1 infection, which is abrogated upon activation. Moreover, our data suggest that bacterial STIs can increase the risk of HIV-1 acquisition in women.

SUBMITTER: van Teijlingen NH

PROVIDER: S-EPMC9968315 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Immune activation of vaginal human Langerhans cells increases susceptibility to HIV-1 infection.

van Teijlingen Nienke H NH Eder Julia J Sarrami-Forooshani Ramin R Zijlstra-Willems Esther M EM Roovers Jan-Paul W R JWR van Leeuwen Elisabeth E Ribeiro Carla M S CMS Geijtenbeek Teunis B H TBH

Scientific reports 20230225 1

Vaginal inflammation increases the risk for sexual HIV-1 transmission but underlying mechanisms remain unclear. In this study we assessed the impact of immune activation on HIV-1 susceptibility of primary human vaginal Langerhans cells (LCs). Vaginal LCs isolated from human vaginal tissue expressed a broad range of TLRs and became activated after exposure to both viral and bacterial TLR ligands. HIV-1 replication was restricted in immature vaginal LCs as only low levels of infection could be det ...[more]

PMID: 36841916

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Project description: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.

Project description:Sexually transmitted infections (STIs) such as herpes simplex virus (HSV)-2 are associated with an increased risk of HIV infection. Human papillomavirus (HPV) is a common STI, but little is know about its role in HIV transmission. The objective of this study was to determine whether cervico-vaginal HPV infection increases the risk of HIV acquisition in women independent of other common STIs.This prospective cohort study followed 2040 HIV-negative Zimbabwean women (average age 27 years, range 18-49 years) for a median of 21 months. Participants were tested quarterly for 29 HPV types (with L1 PCR primers) and HIV (antibody testing on blood samples with DNA or RNA PCR confirmation). HIV incidence was 2.7 per 100 woman-years. Baseline HPV prevalence was 24.5%, and the most prevalent HPV types were 58 (5.0%), 16 (4.7%), 70 (2.4%), and 18 (2.3%). In separate regression models adjusting for baseline variables (including age, high risk partner, positive test for STIs, positive HSV-2 serology and condom use), HIV acquisition was associated with having baseline prevalent infection with HPV 58 (aHR 2.13; 95% CI 1.09-4.15) or HPV 70 (aHR 2.68; 95% CI 1.08-6.66). In separate regression models adjusting for both baseline variables and time-dependent variables (including HSV-2 status, incident STIs, new sexual partner and condom use), HIV acquisition was associated with concurrent infection with any non-oncogenic HPV type (aHR 1.70; 95% CI 1.02-2.85), any oncogenic HPV type (aHR 1.96; 95% CI 1.16-3.30), HPV 31 (aHR 4.25; 95% CI 1.81-9.97) or HPV 70 (aHR 3.30; 95% CI 1.50-7.20). Detection of any oncogenic HPV type within the previous 6 months was an independent predictor of HIV acquisition, regardless of whether HPV status at the HIV acquisition visit was included (aHR 1.95; 95% CI 1.19-3.21) or excluded (aHR 1.96; 95% CI 1.02-2.85) from the analysis.Cervico-vaginal HPV infection was associated with an increased risk of HIV acquisition in women, and specific HPV types were implicated in this association. The observational nature of our study precludes establishment of causation between HPV infection and HIV acquisition. However, given the high prevalence of HPV infection in women, further investigation of the role of HPV in HIV transmission is warranted.

Project description:BackgroundCervical cancer is the fourth most common cancer among women, with persistent high-risk human papillomavirus (HPV) infection being responsible for its progression. In healthy, pre-menopausal women, the vaginal pH value is maintained at 3.8-4.5, but various factors can affect it. Previous studies have suggested the relationship between vaginal pH value and HPV infection. In this study, we aimed to explore the relationship between vaginal pH and susceptibility of HPV infection.MethodsIn our study, we retrospectively collected medical information from women who underwent leukorrhea examination at our hospital. We excluded women with infectious diseases or cancer, those who were pregnant or within 6 months post-delivery, and those without HPV test results within 6 months. The association between percentage of HPV infection and vaginal pH value was analyzed. Furthermore, we prepared HPV pseudovirus (PsVs) by co-transfecting structure plasmids and report plasmids in 293FT cells. In vitro, we changed the pH value of cell culture medium to investigate its influence on HPV PsVs infection. In vivo, we changed mouse's vaginal pH value to investigate its influence on HPV PsVs infection.ResultsOur retrospective study included 3115 women aged 20-78, including 2531 women with HPV negative and 584 women with HPV positive. The percentages of both HPV infection and high-risk HPV infection were higher in women with a vaginal pH value ≥5.0 compared to those with a pH value < 5.0. In vitro, HPV PsVs infection rate was higher in cell culture medium of higher pH value, dominantly due to the influence of pH value on the stage of HPV PsVs adhering to cell surface. Neither of the cell surface HPV receptors Syndecan-1 nor integrin α6 was found to be changed obviously in different pH values. In vivo, more HPV PsVs were adhered to the mouse's vaginal epithelial cells with the increase of the vaginal pH value.ConclusionsOur study suggests a possible association between vaginal pH value and HPV infection. The pH value can influence the susceptibility of HPV PsVs infection by affecting the adhering of HPV PsVs to cells in vivo and in vitro. Additionally, the cell surface HPV receptors Syndecan-1 and Integrin α6 do not seem to be affected by pH value, and the specific mechanism needs to be further explored.

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Immune activation of vaginal human Langerhans cells increases susceptibility to HIV-1 infection.

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Immune activation of vaginal human Langerhans cells increases susceptibility to HIV-1 infection.

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