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1.
J Acquir Immune Defic Syndr ; 74(4): 473-478, 2017 Apr 01.
Article in English | MEDLINE | ID: mdl-28009639

ABSTRACT

BACKGROUND: Type I interferons (IFN1s; eg, interferon-alpha and interferon-beta) are potent cytokines that inhibit the replication of human immunodeficiency virus-1 (HIV-1) and other viruses. The antiviral and immunoregulatory activities of IFN1 are mediated through ligand-receptor interactions with the IFN1 receptor complex (IFNAR). Variation in the cell-surface density of IFNAR could play a role in HIV-1 pathogenesis. METHODS: In this cross-sectional study of fresh whole blood, we used flow cytometry to evaluate the expression of IFNAR2 on lymphocyte subsets from HIV-1-infected (n = 33) and HIV-1-uninfected (n = 22) individuals. RESULTS: In comparison with healthy blood bank donors, we observed that the HIV-1-infected individuals, particularly those having advanced to disease, exhibited the increased expression of IFNAR2 on CD4 T cells (relative fluorescence intensity 6.9 vs. 9.0; P = 0.027). The CD4:CD4 T-cell IFNAR2 expression-level ratio provides an internally standardized measure of this alteration. The observed increased expression of IFNAR2 was largely restricted to CD4 T cells that expressed the chemokine receptor CXCR4 and lacked the expression of CCR5. CONCLUSIONS: HIV-1-infected individuals exhibit an increased expression of the IFN1 receptor on CD4 T cells. The level of IFNAR2 expression seems to increase with disease progression. These findings provide insight for the immunologic alterations associated with HIV-1 infection and possibly new therapeutic approaches.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , HIV Seronegativity/immunology , Receptor, Interferon alpha-beta/blood , Receptors, CCR5/blood , Receptors, CXCR4/blood , Cross-Sectional Studies , Flow Cytometry , Humans , Lymphocyte Activation , Viral Load
2.
AIDS Res Hum Retroviruses ; 29(3): 501-10, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23131038

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)-α 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-α 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-α 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-α production by PDCs from both clinical groups. These findings suggest that differences exist in TLR7- and TLR9-induced IFN-α production by PDCs in HIV-infected individuals that are not directly related to BDCA-2 down-modulation.


Subject(s)
Dendritic Cells/immunology , HIV Infections/immunology , HIV-1/pathogenicity , Toll-Like Receptor 7/agonists , Toll-Like Receptor 9/agonists , Adult , Aged , CD4-Positive T-Lymphocytes/immunology , Female , HIV Infections/pathology , Humans , Interferon-alpha/metabolism , Lectins, C-Type/biosynthesis , Leukocyte Count , Male , Membrane Glycoproteins/biosynthesis , Middle Aged , Receptors, Immunologic/biosynthesis , Toll-Like Receptor 7/immunology , Toll-Like Receptor 9/immunology
3.
AIDS ; 20(9): 1247-52, 2006 Jun 12.
Article in English | MEDLINE | ID: mdl-16816552

ABSTRACT

OBJECTIVES: Reduced dendritic cell (DC) frequencies and functions in individuals with longstanding HIV-1 infection are predictive of opportunistic infections and AIDS. To investigate possible early alterations in DC levels after HIV infection, we prospectively examined plasmacytoid dendritic cell (pDC) and myeloid dendritic cell (mDC) frequencies and plasma IFN-alpha levels in patients undergoing primary HIV-1 infection (PHI). METHODS: Peripheral blood DC frequencies and absolute counts were determined by flow cytometry. Plasma IFN-alpha levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: In comparison to uninfected subjects, pDC, but not mDC, levels were reduced (P < 0.001) in subjects with PHI, especially in those with high viral loads or low CD4 T-cell counts. During 24-48 weeks of observation, untreated subjects experienced slight declines in pDC and CD4 T-cell levels. In contrast, subjects initiating early antiretroviral therapy (ART) exhibited increases (P < 0.001) in pDC and CD4 T-cell counts. No effect of treatment on mDC counts was observed. Circulating plasma IFN-alpha was undetectable by ELISA regardless of the duration of HIV-1 infection. CONCLUSION: PHI is characterized by a reduction in pDC and CD4 T-cell counts that correlates with the magnitude of virus replication and is not evidenced by the mDC count or plasma IFN-alpha level. Early ART appears to have similar restorative effects on pDC and CD4 T-cell counts.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV-1 , Adult , Anti-Retroviral Agents/therapeutic use , CD4 Lymphocyte Count , Dendritic Cells/immunology , Female , Flow Cytometry , HIV Infections/drug therapy , Humans , Interferon-gamma/blood , Lymphocyte Count , Male , Prospective Studies , Statistics, Nonparametric
4.
J Clin Immunol ; 26(1): 55-64, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16418803

ABSTRACT

Plasmacytoid and myeloid dendritic cells are reduced in AIDS patients. The number of these circulating cells was assessed cross-sectionally and longitudinally in 27 uninfected and 72 HIV-infected subjects on and off antiretroviral therapy. The plasmacytoid dendritic cell numbers were significantly reduced in the HIV-infected subjects compared to controls (p < 0.001). This reduction correlated directly with CD4+ cell counts (p < 0.001) and inversely with viral load (p < 0.001). These associations were found to a lesser degree for the myeloid dendritic cells. Intra-assay variability of these dendritic cell counts was < 10%. Antiretroviral therapy significantly increased plasmacytoid dendritic cell (p < 0.001) and CD4+ cell (p = 0.05) counts at 8 months by 76.9% and 19%, respectively. The plasmacytoid dendritic cell levels responded more readily to viral load increases and decreases than CD4+ cells. Circulating plasmacytoid dendritic cells may provide important additional information about immune function in HIV-infected subjects receiving or not receiving antiretroviral therapy.


Subject(s)
Anti-Retroviral Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Dendritic Cells/immunology , HIV Infections/blood , Adult , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/chemistry , Cell Count , Cohort Studies , Female , HIV Infections/drug therapy , HIV Infections/immunology , Humans , Male , Middle Aged , Myeloid Cells/immunology , Plasma Cells/immunology , Viral Load
5.
Virology ; 343(2): 256-66, 2005 Dec 20.
Article in English | MEDLINE | ID: mdl-16278001

ABSTRACT

Plasmacytoid dendritic cells (PDC), natural type-1 interferon (IFN) producing cells, could play a role in the innate anti-HIV immune response. Previous reports indicated that PDC IFN production is induced by HIV. Our results show a more robust IFN induction when purified PDC (>95%) were exposed to HIV-infected cells. This effect was not observed with non-viable cells, DNA, and RNA extracted from infected cells, and viral proteins. The response was blocked by anti-CD4 and neutralizing anti-gp120 antibodies as well as soluble CD4. IFN induction by HIV-infected cells was also prevented by low-dose chloroquine, which inhibits endosomal acidification. PDC IFN release resulted in reduced HIV production by infected CD4+ cells, supporting an anti-HIV activity of PDC. Stimulated CD4+ cells induced PDC activation and maturation; markers for PDC migration (CCR7) were enhanced by HIV-infected CD4+ cells only. This latter finding could explain the decline in circulating PDC in HIV-infected individuals.


Subject(s)
Dendritic Cells/immunology , HIV Infections/immunology , Interferon Type I/biosynthesis , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , Cell Communication/immunology , Cell Differentiation , Cell Movement , Coculture Techniques , Dendritic Cells/pathology , Dendritic Cells/physiology , Endocytosis , HIV Infections/pathology , HIV Infections/physiopathology , HIV-1/immunology , HIV-1/physiology , Humans , Immunity, Innate , Plasma Cells/immunology , Plasma Cells/pathology , Plasma Cells/physiology
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