Abstract
Dendritic cells (DCs) contribute to human immunodeficiency virus type 1 (HIV-1) transmission and dissemination by capturing and transporting infectious virus from the mucosa to draining lymph nodes, and transferring these virus particles to CD4+ T cells with high efficiency. Toll-like receptor (TLR)-induced maturation of DCs enhances their ability to mediate trans-infection of T cells and their ability to migrate from the site of infection. Because TLR-induced maturation can be inhibited by nuclear receptor (NR) signaling, we hypothesized that ligand-activated NRs could repress DC-mediated HIV-1 transmission and dissemination. Here, we show that ligands for peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor (LXR) prevented proinflammatory cytokine production by DCs and inhibited DC migration in response to the chemokine CCL21 by preventing the TLR-induced upregulation of CCR7. Importantly, PPARγ and LXR signaling inhibited both immature and mature DC-mediated trans-infection by preventing the capture of HIV-1 by DCs independent of the viral envelope glycoprotein. PPARγ and LXR signaling induced cholesterol efflux from DCs and led to a decrease in DC-associated cholesterol, which has previously been shown to be required for DC capture of HIV-1. Finally, both cholesterol repletion and the targeted knockdown of the cholesterol transport protein ATP-binding cassette A1 (ABCA1) restored the ability of NR ligand treated cells to capture HIV-1 and transfer it to T cells. Our results suggest that PPARγ and LXR signaling up-regulate ABCA1-mediated cholesterol efflux from DCs and that this accounts for the decreased ability of DCs to capture HIV-1. The ability of NR ligands to repress DC mediated trans-infection, inflammation, and DC migration underscores their potential therapeutic value in inhibiting HIV-1 mucosal transmission.
Highlights
Worldwide, heterosexual transmission accounts for most new human immunodeficiency virus type 1 (HIV-1) infections, with a majority of these occurring in developing countries [1,2]
Virus capture was measured by p24gag ELISA. (n = 3) (D) immature MDDCs (iMDDCs) were treated with 100 mM ciglitazone or 1 mM TO-901317 for various times, incubated with HIV-1ADA, and assayed for virus capture by p24gag ELISA. (n = 3) (E) Immature monocytederived DCs (MDDCs) were treated with ciglitazone (100 mM) or TO-901317 (1 mM) for 48 hours, incubated with HIV-1ADA for four hours at 37uC, and washed to remove unbound virus
Sexual transmission of HIV-1 is enhanced by inflammatory and ulcerative co-infections with STI pathogens that cause diseases such as genital herpes, gonorrhea, syphilis, Chlamydia, bacterial vaginosis, and fungal infections [78,79,80,81,82,83]. This enhanced susceptibility to infection may be due to a number of factors, including disruption of epithelial integrity [6,11,14,84,85,86,87], recruitment of HIV-1 target cells such as Langerhans cells, Dendritic cells (DCs), macrophages, and T lymphocytes to sites of inflammation [8], and iMDDCs were treated for 48 hours with 100 mM ciglitazone or 1 mM TO-901317 and cholesterol efflux into the culture supernatant was measured
Summary
Heterosexual transmission accounts for most new HIV-1 infections, with a majority of these occurring in developing countries [1,2]. Immune cells within the vaginal, cervical, or rectal mucosa are thought to be the primary targets of infection in the sexual transmission of HIV-1 [1,3,4]. These target cells include subepithelial CD4+ T lymphocytes, intra-epithelial Langerhans cells, macrophages, submucosal plasmacytoid DCs (pDCs), and myeloid (or conventional) DCs (mDCs) located within the lamina propria [4,5,6,7,8,9,10,11]. Recent reports have demonstrated that DCs matured by exposure to pathogens encoding Toll-like receptor (TLR) ligands or to proinflammatory cytokines are capable of enhanced HIV-1 transinfection [23,24,25] and chemokine-directed migration [26,27], suggesting that agents capable of preventing inflammation and DC maturation may be able to limit HIV-1 transmission and dissemination
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