TNF-α and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo

Jong, Marein A. W. P. de; Witte, Lot de; Oudhoff, Menno J.; Gringhuis, Sonja I.; Gallay, Philippe; Geijtenbeek, Teunis B. H.

doi:10.1172/jci34721

Cited by 119 publications

(203 citation statements)

References 56 publications

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“…HIV-1 viruses R5-tropic enhanced GFP (eGFP)-expressing HIV-1-NL4.3-BaL (referred to as HIV-1-eGFP) (20 ng/well) and replication-defective R5-tropic pseudotyped HIV-1 (HIV-1 BaL-pseudotyped NL4.3-eGFPDENV) (50 ng/well) were produced in 293T cells, as described previously (16). Virus stocks were quantified by p24 ELISA (PerkinElmer, Wellesley, MA) and titrated using the indicator cells TZM-blue (16,20).…”

Section: Cell Lines and Virusesmentioning

confidence: 99%

“…Virus stocks were quantified by p24 ELISA (PerkinElmer, Wellesley, MA) and titrated using the indicator cells TZM-blue (16,20).…”

Section: Cell Lines and Virusesmentioning

confidence: 99%

“…An LCenriched epidermal single-cell suspension was generated, as described previously (15,16). In short, epidermis was separated after dispase II (1 mg/ ml; Roche Diagnostic Systems, Somerville, NJ) treatment and digested in 0.05% trypsin solution.…”

Section: Isolation Of Epidermal Single-cell Suspension and Lcsmentioning

confidence: 99%

“…cDNA was synthesized with the Reverse Transcriptase Kit (Promega, Madison, WI). For quantitative realtime PCR analysis, PCR amplification was performed in the presence of SYBR green, as previously described (16,25). Specific primers for HSV-2 thymidine kinase and GAPDH were designed by Primer Express 2.0 (Applied Biosystems, Foster City, CA): forward primer sequence, 59-CGA-GCCGATGACTTACTGGC-39; reverse primer sequence, 59-GCTGCGTGTT-GTAGATGTTCG-39.…”

Section: Hsv-2 Mrna Transcriptionmentioning

confidence: 99%

“…Thus, LCs form a first line of defense against HIV-1 infection. However, inhibition of the antiviral function of langerin or inflammatory conditions allows infection of LCs by HIV-1, and infected LCs efficiently transmit HIV-1 to T cells (15,16). Therefore, we hypothesized that viral STIs, such as HSV-2, increase HIV-1 susceptibility by affecting the protective function of LCs.…”

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confidence: 99%

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Herpes Simplex Virus Type 2 Enhances HIV-1 Susceptibility by Affecting Langerhans Cell Function

Jong

Witte

Taylor

et al. 2010

The Journal of Immunology

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Genital herpes is the most prevalent viral sexually transmitted infection worldwide and is mainly caused by HSV type 2 (HSV-2). HSV-2 infection enhances HIV-1 susceptibility, even in the absence of clinical symptoms. In this study, we investigated the effect of HSV-2 on HIV-1 transmission by mucosal Langerhans cells (LCs). LCs are important in heterosexual transmission because they form a barrier against HIV-1 infection; LCs efficiently capture and degrade HIV-1 through the C-type lectin langerin, thereby preventing HIV-1 transmission. Notably, our data showed that HSV-2 enhanced HIV-1 infection of LCs and subsequent HIV-1 transmission to T cells. HSV-2 interfered with HIV-1 capture by langerin, which allowed efficient HIV-1 infection of LCs. HSV-2 inhibited the antiviral function of langerin at two levels; HSV-2 decreased langerin expression and competed with HIV-1 for langerin binding. HSV-2 replication was not required, because both UV-inactivated HSV-2 and TLR-3 agonist polyinosinic:polycytidylic acid similarly increased HIV-1 transmission by LCs. Therefore, we identified a mechanism by which HSV-2 enhances HIV-1 susceptibility, even in the absence of clinical symptoms. Our data demonstrated that viral coinfections, such as HSV-2, breach the protective function of LCs by abrogating langerin function, which increases HIV-1 susceptibility. These data reinforce the importance of preventing sexually transmitted infections, such as HSV-2, to reduce the transmission of HIV-1.

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Section: Cell Lines and Virusesmentioning

confidence: 99%

“…Virus stocks were quantified by p24 ELISA (PerkinElmer, Wellesley, MA) and titrated using the indicator cells TZM-blue (16,20).…”

Section: Cell Lines and Virusesmentioning

confidence: 99%

Section: Isolation Of Epidermal Single-cell Suspension and Lcsmentioning

confidence: 99%

Section: Hsv-2 Mrna Transcriptionmentioning

confidence: 99%

mentioning

confidence: 99%

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Herpes Simplex Virus Type 2 Enhances HIV-1 Susceptibility by Affecting Langerhans Cell Function

Jong

Witte

Taylor

et al. 2010

The Journal of Immunology

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Blocking of integrins inhibits HIV‐1 infection of human cervical mucosa immune cells with free and complement‐opsonized virions

et al. 2013

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The initial interaction between HIV-1 and the host occurs at the mucosa during sexual intercourse. In cervical mucosa, HIV-1 exists both as free and opsonized virions and this might influence initial infection. We used cervical explants to study HIV-1 transmission, the effects of opsonization on infectivity, and how infection can be prevented. Complement opsonization enhanced HIV-1 infection of dendritic cells (DCs) compared with that by free HIV-1, but this increased infection was not observed with CD4+ T cells. Blockage of the α4-, β7-, and β1-integrins significantly inhibited HIV-1 infection of both DCs and CD4+ T cells. We found a greater impairment of HIV-1 infection in DCs for complement-opsonized virions compared with that of free virions when αM/β2- and α4-integrins were blocked. Blocking the C-type lectin receptor macrophage mannose receptor (MMR) inhibited infection of emigrating DCs but had no effect on CD4+ T-cell infection. We show that blocking of integrins decreases the HIV-1 infection of both mucosal DCs and CD4+ T cells emigrating from the cervical tissues. These findings may provide the basis of novel microbicidal strategies that may help limit or prevent initial infection of the cervical mucosa, thereby reducing or averting systemic HIV-1 infection.

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

et al. 2019

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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.

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TNF-α and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo

Cited by 119 publications

References 56 publications

Herpes Simplex Virus Type 2 Enhances HIV-1 Susceptibility by Affecting Langerhans Cell Function

Herpes Simplex Virus Type 2 Enhances HIV-1 Susceptibility by Affecting Langerhans Cell Function

Blocking of integrins inhibits HIV‐1 infection of human cervical mucosa immune cells with free and complement‐opsonized virions

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

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