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 7

Pam3CSK4 increases HIV-1 capture and primarily transmits cell-bound HIV-1.

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Pam3CSK4 increases HIV-1 capture and primarily transmits cell-bound HIV-...
(A and B) Emigrant LCs were stimulated with Pam3CSK4 for 1 hour and inoculated with NL4.3 BaL. After 2 hours, cells were extensively washed. The cells were fixed, permeabilized, and stained for the LC-marker CD1a and HIV-1 p24. The cells were counterstained with isotype-specific Alexa antibodies (red, HIV-1 p24; green, CD1a). Single HIV-1 particles are indicated with arrows. Original magnification, ×630. A representative experiment out of 2 is depicted. (C and D) Epidermal single-cells suspensions were stimulated with Pam3CSK4. After 6 hours, cells were inoculated with single-cycle HIV-1. After 2 hours, the cell suspensions were washed, and subsequently cells were treated with trypsin at 37°C to remove cell-bound HIV-1 or a PBS control (C), or with HIV-1 neutralizing antibody b12 at 4°C to neutralize cell-bound, but not internalized, HIV-1 and an isotype control (D). Cells were washed and CCR5+ Jurkat T cells were added. At day 5, the cocultures were analyzed for GFP expression by flow cytometry. A representative experiment out of 3 is depicted. Errors bars represent the SD of duplicates. (E) Epidermal single-cells suspension was stimulated with TNF-α or Pam3CSK4 before being inoculated with different concentrations of HIV-1–eGFP. After 2 hours, the cell suspensions were washed, and CCR5+ Jurkat T cells were added. HIV-1 transmission was followed by flow cytometry. A representative experiment out of 2 donors is depicted. Error bars represent the mean ± SD of duplicates. TCID, tissue-culture infectious dose.