Plasmacytoid Dendritic Cell Number and Responses to Toll-Like Receptor 7 and 9 Agonists Vary in HIV Type 1-Infected Individuals in Relation to Clinical State

Abstract

In HIV-1 infection, plasmacytoid dendritic cell (PDC) numbers and function are decreased. No detailed comparisons of PDC responses to various stimuli in HIV-1-infected patients are available. Using for the first time purified PDCs, we compared PDC responses [interferon (IFN)-a production/cell] to various stimuli in a large number (n = 48) of HIV-1-infected patients and healthy volunteers (n = 19). Toll-like receptor (TLR)7-and TLR9-induced expression of PDC surface activation and maturation markers was also compared in the two populations. We have confirmed that PDC number coincides with CD4 + T cell counts and clinical state. Notably, we have shown that a direct association of PDC function in terms of IFN-a production/cell exists with PDC numbers and CD4+ cell counts when PDCs are exposed to a TLR9 ligand and HIV-infected cells, but not with a TLR7 ligand. Moreover, in the HIV-infected subjects but not the healthy controls, the magnitude of IFN-a release per PDC in response to the TLR7 ligand is significantly ( p < 0.01) lower than that to the TLR9 ligand. However, in both study populations, the TLR7 stimulation in comparison to TLR9 stimulation induced higher expression of PDC surface activation and maturation markers and significantly ( p < 0.05) decreased the expression of BDCA-2, a negative regulator of interferon. Furthermore, the cross-ligation of BDCA-2 significantly ( p < 0.05) inhibited TLR9-but not TLR7-induced IFN-a production by PDCs from both clinical groups. These findings suggest that differences exist in TLR7-and TLR9-induced IFN-a production by PDCs in HIV-infected individuals that are not directly related to BDCA-2 down-modulation.

Increased proportions of dendritic cells and recovery of IFNγ responses in HIV/HCV co-infected patients receiving ART

“…No associations between DC percentages and CD4 + T-cell counts were found. This contradicts previous studies that reported a positive correlation between DC numbers with CD4 + T-cell counts in untreated and treated chronically HIV-infected individuals [5,41,42], patients with primary HIV infection [15], a cohort comprising HIV and HIV/HCV coinfected patients [24] and in a longitudinal study that followed HIV-infected patients during 60 weeks of ART [40]. The absence of a correlation probably reflects selection bias as all participants in our study started ART with CD4 + T-cell counts <200 cells/L, whereas prior cross-sectional studies included patients with a wider range of baseline CD4 + T-cell counts.…”

“…Our data showing an inverse association between DC frequencies and HIV viral loads is consistent with previous studies [15,41,42] and is consistent with a role for DC in the control of HIV replication. This may involve the antiviral cytokine, IFN, present at higher levels in HIV controllers than viremic patients [43].…”

Tim-3 is a Marker of Plasmacytoid Dendritic Cell Dysfunction during HIV Infection and Is Associated with the Recruitment of IRF7 and p85 into Lysosomes and with the Submembrane Displacement of TLR9

“…Many cancers, autoimmune disorders, and chronic infections are associated with decreased responsiveness of pDCs to TLR agonists (5,(11)(12)(13)(14). This dysfunction of the pDC response is well documented in the context of HIV type 1 infection (15)(16)(17)(18)(19)(20)(21). The role of pDCs during HIV infection is complex and not fully understood (5,7).…”

Dendritic cells primed with a chimeric plasmid containing HIV‐1‐ gag associated with lysosomal‐associated protein‐1 (LAMP/ gag ) is a potential therapeutic vaccine against HIV

“…Diminished levels and dysfunctional dendritic cells (DCs) are also frequently observed and may contribute to an overall impairment of adaptive immunity (6)(7)(8).…”