Persistent Decreases in Blood Plasmacytoid Dendritic Cell Number and Function Despite Effective Highly Active Antiretroviral Therapy and Increased Blood Myeloid Dendritic Cells in HIV-Infected Individuals

Abstract

Dendritic cells (DC) have an instrumental role in the activation and function of both innate and adaptive immune responses. In humans, at least two distinct DC subsets have been characterized based on phenotypic markers: the myeloid DC (MDC) and the plasmacytoid DC (PDC). Both subsets are critical producers of cytokines (IL-12 for MDC and type I/II IFNs for PDC) and are functionally different. We show in this study that HIV+ individuals have a significant decrease in the number of the Lin−HLA-DR+CD123+ and BDCA-2+ PDC compared with uninfected donors (p = 0.0001). HIV+ individuals also have a sustained impairment in viral-induced IFN-α production (p < 0.0001). The decrease of the PDC subsets did not correlate with CD4 count or viral load and was not reversed in subjects under virally suppressive treatment, suggesting an irreversible change after infection. By contrast, the absolute number and median frequency of MDC in HIV-infected individuals were similar to those observed in uninfected controls, while a significant decrease was present in subjects with >5000 HIV-1 copies/ml. The inverse association with viral load of the MDC number, but not of IFN-α secretion or the number of PDC, suggests a role for MDC in viral control. Our data suggest that DC subsets are differentially reconstituted during the immune recovery associated with antiviral therapy. The persistent impairment of certain DC subsets may result in a sustained defect in DC-mediated innate immune functions despite an effective treatment regimen.

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

“…3A) stimulated with the TLR7 and TLR7/8 agonists. A reduced frequency of pDC in HIV + individuals which is consistent with previously published reports (6,26,27,35), may be responsible for the lower concentrations of IFN-α detected in HIV-1 infected individuals. To discriminate between qualitative and quantitative abnormalities in pDC function, we measured the intracellular expression of IFN-α at the single cell level using a broad range of synthetic and natural TLR ligands.…”

“…Previous studies have shown impaired IFN-α secretion by pDC and defective monocyte maturation post-TLR9 (CpG ODN) stimulation in HIV-1-infected individuals (26,35,44). To expand on these studies we demonstrated a dysregulation in total IFN-α (pg/ml) secretion in PBMC cultures from HIV + individuals (Fig.…”

“…HIV-1 infection is associated with low numbers of circulating pDC in the peripheral blood (6,26,27,35) which may lead to impaired innate immune function and diminished initiation of adaptive immunity. We incubated PBMC with synthetic small molecule imidazoquinolines that are TLR7 and TLR8 agonists and evaluated in vitro activation and maturation of pDC from HIV + and HIV − individuals.…”

IFN-α production by human mononuclear cells infected with varicella-zoster virus through TLR9-dependent and -independent pathways

“…In contrast, pDCs express CD123, BDCA-2 and BDCA-4 antigens. 7,8 They also express different patterns of pathogen recognition receptors and respond to different microbial antigens. The main function of pDCs appears to be the production of a large amount of type I interferons (IFNs) in response to infection.…”

Decreased Stimulation of CD4+ T Cell Proliferation and IL-2 Production by Highly Enriched Populations of HIV-Infected Dendritic Cells

“…Another important issue in the field of DC-HIV biology is that data derived from studies using particular subtypes of DC (e.g., Langerhans cells vs monocyte-derived DC, immature vs mature DC, myeloid vs plasmacytoid DC) have clearly demonstrated disparate results. Regarding the immunologic function of HIV-infected DC or of DC isolated from HIV-infected individuals, existing literature on this topic is also varied (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Some have claimed significant APC defects and others none.…”