Dendritic cells from HIV-1 infected individuals are less responsive to toll-like receptor (TLR) ligands

Abstract

We compared TLR responsiveness in PBMC from HIV-1-infected and uninfected individuals using the TLR agonists: TLR7 (3M-001), TLR8 (3M-002) and TLR7/8 (3M-011). Activation and maturation of plasmacytoid dendritic cells (pDC)were measured by evaluating CD86, CD40 and CD83 expression and myeloid dendritic cell (mDC) activation was measured by evaluating CD40 expression. All agonists tested induced activation and maturation of pDC in PBMC cultures of cells from HIV+ and HIV− individuals. The TLR7 agonist induced significantly less pDC maturation in cells from HIV+ individuals. Quantitative assessment of secreted IFN-α and pro-inflammatory cytokines at the single cell level showed that pDC from HIV+ individuals stimulated with TLR7 and TLR7/8 induced IFN-α. TLR8 and TLR7/8 agonists induced IL-12 and COX-2 expression in mDC from HIV+ and HIV− individuals. Understanding pDC and mDC activation and maturation in HIV-1 infection could lead to more rational development of immunotherapeutic strategies to stimulate the adaptive immune response to HIV-1.

HIV Type 1 Infection Up-Regulates TLR2 and TLR4 Expression and Function in Vivo and in Vitro

“…The results are in accordance with the previously reported by Martinson et al (2007) about the higher expression of the activation and maturation markers CD40, CD83, and CD86 on pDC, in response to TLR7/8 stimulation; but they fail to show the overexpression of these molecules in HIV-1-infected patients, compared to healthy donors. 41 In contrast, they found a decrease in IFN-a production in response to TLR7/TLR8 stimulation in HIV-1-infected patients, compared to healthy donors.…”

“…41 In contrast, they found a decrease in IFN-a production in response to TLR7/TLR8 stimulation in HIV-1-infected patients, compared to healthy donors. 41 Interestingly, TLR stimulation can also activate CD4 + and CD8 + T lymphocytes, determined by the expression of CD38, and even induce the central memory and effector CD4 + T cells to enter into cell cycle, and after activation can also induce apoptosis in CD4 + T cells. 42 Remarkably, modulation of TLRs expression after HIV-1 infection behaved differently.…”

“…3C), similar to TNF-a, IL-12, and COX-2 in mDC from HIV-1-infected patients, previously reported. 41 Based on these findings, we can speculate that HIV-1 has developed strategic mechanisms to alter the expression of TLRs and enhance proinflammatory cytokine production, which could play a key role in immune pathogenesis. However, it can also be argued that high expression of TLR2 and TLR4 in cells from HIV-1-infected patients, or in PBMCs from healthy subjects HIV-1 infected in vitro, results in increased HIV-1 replication.…”

Differential Interleukin-10 (IL-10) and IL-23 Production by Human Blood Monocytes and Dendritic Cells in Response to Commensal Enteric Bacteria

“…Conversely, although the median percentage of mDC expressing CD83 was increased in response to bacteria compared to the level in the medium-only control, the increase did not reach statistical significance for any of the bacteria (E. coli, P ϭ 0.44; Enterococcus, P ϭ 0.31; B. fragilis, P ϭ 0.09). It was noted that the frequency of CD83 ϩ mDC markedly increased in cultures without exogenous stimulation (medium-only control) relative to that measured directly ex vivo, resulting in high background expression, as reported by others (36).…”

Chloroquine Modulates HIV-1-Induced Plasmacytoid Dendritic Cell Alpha Interferon: Implication for T-Cell Activation

“…The concentration of HIV-1 (500 ng/ml) used in this study is within the range found in the plasma of infected individuals (including children and adults), which is known to vary depending on the stage of HIV disease (44,66). Optimal concentrations of the TLR agonists (32,54,55) and AT-2 HIV-1 (54) have been determined previously. Media and matched microvesicle controls, MV-CCR5 and MV-CEMX, served as the negative controls in these experiments.…”