Impact of in vitro Costimulation with TLR2, TLR4 and TLR9 Agonists and HIV-1 on Antigen-Presenting Cell Activation

Abstract

Objective: HIV-1 infects several immune cells including dendritic cells (DCs) and monocytes, which contributes in both to dissemination of HIV-1 infection and induction of antiviral immunity. These cells produce high amounts of type I IFN and proinflammatory cytokines upon Toll-like receptor (TLR) stimulation. During HIV-1 infection, an altered production of proinflammatory cytokines has been reported. However, the mechanisms underlying cytokine modulation have not been well described. Here, we evaluated the production of proinflammatory cytokines and activation of myeloid and plasmacytoid DCs and monocytes costimulated in vitro with TLR agonists and HIV-1. Methods: Changes in cytokine expression by real-time PCR and activation of DCs and monocytes by flow cytometry were evaluated after costimulation with HIV-1 and TLR agonists. Results: We observed an upregulation of TNF-α expression after TLR4 stimulation, but a downregulation of IL-6 when TLR2/TLR9 were stimulated. Interestingly, the expression of CD80 and CD86 costimulatory molecules in monocytes and DCs were significantly increased in cells challenged with HIV-1 and TLR2/TLR4/TLR9 agonists. Conclusion: This regulation of TNF-α and IL-6 production and changes in the expression of costimulatory molecules can be critical in the context of HIV-1 infection, by favoring the antigen-presenting cell activation through the stimulation of TLRs.

Expressions of toll-like receptors 2 and 4, and relative cellular factors in HIV patients with tuberculosis infection

“…This shows that HIV infection up-regulates TLR2 and TLR4 expressions. This finding is in agreement with previous reports [17,18]. The TLR-2 mRNA level of HIV patients with TB infection was higher when compared with its value in the HIV group, but there were no differences in TLR4 mRNA between the two groups.…”

Protein Expression of TLR2, TLR4, and TLR9 on Monocytes in TB, HIV, and TB/HIV

“…Previous studies have evaluated levels of TLR mRNA in diseased participants [ 7 , 9 , 26 – 28 ]. We report here the protein expression of TLRs on cells in patients with HIV and TB/HIV coinfection.…”

“…In vitro and in vivo studies demonstrated that intermediate monocytes produce high level of proinflammatory cytokines such as IL1 β , TNF α , and IL6 [ 39 – 41 ] thus it is more likely that TLRs expressed on intermediate monocytes to correlate with inflammatory cytokines. In vitro studies on PBMCs and alveolar macrophages demonstrated differential induction of cytokines in response to TLR agonists [ 28 , 42 ]. Stimulation of alveolar macrophages with several responding TLR agonists resulted in strong TLR4-dependent immune response with massive cytokine and chemokine genes expression (CCL2, CCL3, CCL4, CXCL10, TNF α , IL6, and IL10) while moderate level TLR2 dependent immune response with fewer gene expressions but weaker TLR9 dependent responses [ 42 ].…”

“…Stimulation of alveolar macrophages with several responding TLR agonists resulted in strong TLR4-dependent immune response with massive cytokine and chemokine genes expression (CCL2, CCL3, CCL4, CXCL10, TNF α , IL6, and IL10) while moderate level TLR2 dependent immune response with fewer gene expressions but weaker TLR9 dependent responses [ 42 ]. In another study, PBMCs stimulated with TLR2, TLR4, and TLR9 agonists along with HIV-1 virus resulted in the induction of TNF α and IL6 mRNA in TLR4-dependent manner but reduced IL6 mRNA in TLR2 and TLR9 based activation [ 28 ].…”