TNF-α and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo
Marein A.W.P. de Jong, … , Philippe Gallay, Teunis B.H. Geijtenbeek
Marein A.W.P. de Jong, … , Philippe Gallay, Teunis B.H. Geijtenbeek
Published September 5, 2008
Citation Information: J Clin Invest. 2008;118(10):3440-3452. https://doi.org/10.1172/JCI34721.
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Research Article AIDS/HIV

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

Abstract

Genital coinfections increase an individual’s risk of becoming infected with HIV-1 by sexual contact. Several mechanisms have been proposed to explain this, such as the presence of ulceration and bleeding caused by the coinfecting pathogen. Here we demonstrate that Langerhans cells (LCs) are involved in the increased susceptibility to HIV-1 in the presence of genital coinfections. Although LCs are a target for HIV-1 infection in genital tissues, we found that immature LCs did not efficiently mediate HIV-1 transmission in an ex vivo human skin explant model. However, the inflammatory stimuli TNF-α and Pam3CysSerLys4 (Pam3CSK4), the ligand for the TLR1/TLR2 heterodimer, strongly increased HIV-1 transmission by LCs through distinct mechanisms. TNF-α enhanced transmission by increasing HIV-1 replication in LCs, whereas Pam3CSK4 acted by increasing LC capture of HIV-1 and subsequent trans-infection of T cells. Genital infections such as Candida albicans and Neisseria gonorrhea not only triggered TLRs but also induced TNF-α production in vaginal and skin explants. Thus, during coinfection, LCs could be directly activated by pathogenic structures and indirectly activated by inflammatory factors, thereby increasing the risk of acquiring HIV-1. Our data demonstrate a decisive role for LCs in HIV-1 transmission during genital coinfections and suggest antiinflammatory therapies as potential strategies to prevent HIV-1 transmission.

Authors

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

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Figure 3

TNF-α and Pam3CSK4 enhance HIV-1 transmission ex vivo.

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TNF-α and Pam3CSK4 enhance HIV-1 transmission ex vivo. (A–D) Epidermal s...
(A–D) Epidermal sheets were stimulated with TNF-α, Pam3CSK4, LTA, LPS, or flagellin for 6 hours, and ex vivo transmission was determined as in Figure 1. (A) Cocultures of donors number 1–4 (day 7) were analyzed for GFP expression by flow cytometry. HIV-1 transmission is depicted as percentage of CCR5+ Jurkat T cells positive for GFP expression. Error bars represent the mean ± SD of duplicates. (B) Results obtained with donors number 1–8 are depicted, and the values were analyzed for statistical differences by ANOVA (**P < 0.01, ***P < 0.001 versus the no treatment condition). (C) Before addition of the CCR5+ Jurkat T cells the migrated cells were extensively washed. At day 7, supernatant was collected, and viral content was monitored by p24 ELISA. A representative experiment of 2 is depicted. (D) To analyze donor differences, 4 different skin donors were incubated with TNF-α, LTA, LPS, or flagellin at 2 different days, and ex vivo transmission was determined as described in Figure 1. The samples were measured for 13 days. Error bars represent the mean ± SD of duplicates.