Influence of Plasma Viremia on Defects in Number and Immunophenotype of Blood Dendritic Cell Subsets in Human Immunodeficiency Virus 1–Infected Individuals

Department of Medicine, University of Colorado, Denver, Colorado, United States
The Journal of Infectious Diseases (Impact Factor: 5.78). 02/2003; 187(1):26-37. DOI: 10.1086/345957
Source: PubMed

ABSTRACT Dendritic cells (DCs) are postulated to be involved in transmission of human immunodeficiency virus (HIV) type 1 to T cells and in stimulation of HIV-1-specific cell-mediated immunity. Blood DCs have been categorized as myeloid (mDC) and plasmacytoid (pDC) subsets, on the basis of differences in phenotype and function. Blood DC subset numbers and expression of costimulatory molecules and HIV-1 coreceptors on DCs were measured in the blood of treated and untreated HIV-1-infected subjects and uninfected control subjects. Absolute numbers of mDCs and pDCs were lower in HIV-1-infected subjects than in control subjects, most significantly in those with active HIV-1 replication. Increased surface expression of costimulatory molecules was observed on both DC subsets in subjects with HIV-1 viremia. Highly active antiretroviral therapy suppression of plasma viremia resulted in increases in blood DC numbers and decreases in DC costimulatory molecule expression. These findings further define the impact of HIV-1 replication on blood DC subsets in vivo.

  • Source
    • "In HIV infection it has been demonstrated a reduction in absolute number of mDC and pDC, especially in patients with active HIV-1 replication [3], suggesting a key role of DC in controlling viral load. Moreover the preserved functionality of pDC isolated from “elite controllers” may be one of the mechanisms involved in the control of HIV-1 viremia in these subjects [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: NLRP3-inflammasome activation was evaluated in monocyte-derived dendritic cells (DC) obtained through IL-4 (IL4-DC) or IFN-alpha (IFN-DC) protocols and pulsed with chemically inactivated HIV-1. Inflammasome' genes expression and IL-1ss secretion were compared in DC isolated from 15 healthy subjects (HC) and 10 HIV-1 infected individuals (HIV+). Whether HIV was able to increased NLRP3-inflammasome genes expression and IL-1ss secretion in IL4-DC from HC, the induction of inflammasome appeared significantly reduced in IFN-DC from HC, suggesting a different responsive state of IFN-DC compared to IL4-DC. No inflammasome activation was observed in IL4-DC as well as in IFN-DC derived from HIV + subjects, confirming previous findings on "unresponsive" state of DC derived from HIV + possibly due to chronic inflammatory state of these individuals. Our results showed that IFN-alpha differently modulates inflammasome expression during monocytes-DC in vitro differentiation. These findings could be of interest considering the on-going research about DC manipulation and therapeutic strategies for HIV + involving DC-based immune-vaccines.
    AIDS Research and Therapy 12/2013; 10(1):35. DOI:10.1186/1742-6405-10-35 · 1.84 Impact Factor
  • Source
    • "This includes low CD4 T cell counts, CD4 T cell expression of markers associated with activation and exhaustion [14], [30], as well as CD8 T cell activation [9], [10], [11], [12], [13], [14]. Likewise, the patterns of decreased levels of mDCs [31], [32], [33], Treg cells [34], [35] and iNKT cells [36], [37], [38], increased PD-1 expression on iNKT cells [39], as well as increased plasma levels of sCD14 [14], [40], in CVID patients are shared with HIV-1 infected patients. Interestingly, it was previously reported that CVID patients with lower naïve CD4 T cell levels display worse clinical scores [41], and, in line with the present data, that CVID patients display a pattern of L-selectin and CD38 expression on CD8 T cells similar to that observed in HIV-1 infected patients [42]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Common variable immunodeficiency (CVID) is characterized by defective B cell function, impaired antibody production, and increased susceptibility to bacterial infections. Here, we addressed the hypothesis that poor antibody-mediated immune control of infections may result in substantial perturbations in the T cell compartment. Newly diagnosed CVID patients were sampled before, and 6-12 months after, initiation of intravenous immunoglobulin (IVIg) therapy. Treatment-naïve CVID patients displayed suppressed CD4 T cell counts and myeloid dendritic cell (mDC) levels, as well as high levels of immune activation in CD8 T cells, CD4 T cells, and invariant natural killer T (iNKT) cells. Expression of co-stimulatory receptors CD80 and CD83 was elevated in mDCs and correlated with T cell activation. Levels of both FoxP3+ T regulatory (Treg) cells and iNKT cells were low, whereas soluble CD14 (sCD14), indicative of monocyte activation, was elevated. Importantly, immune reconstitution treatment with IVIg partially restored the CD4 T cell and mDC compartments. Treatment furthermore reduced the levels of CD8 T cell activation and mDC activation, whereas levels of Treg cells and iNKT cells remained low. Thus, primary deficiency in humoral immunity with impaired control of microbial infections is associated with significant pathological changes in cell-mediated immunity. Furthermore, therapeutic enhancement of humoral immunity with IVIg infusions alleviates several of these defects, indicating a relationship between poor antibody-mediated immune control of infections and the occurrence of abnormalities in the T cell and mDC compartments. These findings help our understanding of the immunopathogenesis of primary immunodeficiency, as well as acquired immunodeficiency caused by HIV-1 infection.
    PLoS ONE 10/2013; 8(10):e75199. DOI:10.1371/journal.pone.0075199 · 3.23 Impact Factor
  • Source
    • "Untreated chronic HIV-1-infected patients under HAART recovered mDC numbers in contrast to a sustained loss of pDCs in parallel with decreased IFN-α secretion [42], [43]. The decline of pDCs inversely correlates with viral load and is associated with a decrease in the level of IFN-α production per cell and lower CD4+ T cell counts [44], [45]. Evidence of immune exhaustion in pDCs and a better reconstitution of pDCs in patients treated with HAART early argue that an earlier start to therapy results in preservation of pDC numbers and function [46]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mother-to-child transmission (MTCT) of HIV-1 has been significantly reduced with the use of antiretroviral therapies, resulting in an increased number of HIV-exposed uninfected infants. The consequences of HIV infection on the innate immune system of both mother-newborn are not well understood. In this study, we analyzed peripheral blood and umbilical cord blood (CB) collected from HIV-1-infected and uninfected pregnant women. We measured TNF-α, IL-10 and IFN-α secretion after the stimulation of the cells with agonists of both extracellular Toll-like receptors (TLRs) (TLR2, TLR4 and TLR5) and intracellular TLRs (TLR7, TLR7/8 and TLR9). Moreover, as an indicator of the innate immune response, we evaluated the responsiveness of myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) to TLRs that are associated with the antiviral response. Our results showed that peripheral blood mononuclear cells (PBMCs) from HIV-1-infected mothers and CB were defective in TNF-α production after activation by TLR2, TLR5, TLR3 and TLR7. However, the TNF-α response was preserved after TLR7/8 (CL097) stimulation, mainly in the neonatal cells. Furthermore, only CL097 activation was able to induce IL-10 and IFN-α secretion in both maternal and CB cells in the infected group. An increase in IFN-α secretion was observed in CL097-treated CB from HIV-infected mothers compared with control mothers. The effectiveness of CL097 stimulation was confirmed by observation of similar mRNA levels of interferon regulatory factor-7 (IRF-7), IFN-α and TNF-α in PBMCs of both groups. The function of both mDCs and pDCs was markedly compromised in the HIV-infected group, and although TLR7/TLR8 activation overcame the impairment in TNF-α secretion by mDCs, such stimulation was unable to reverse the dysfunctional type I IFN response by pDCs in the HIV-infected samples. Our findings highlight the dysfunction of innate immunity in HIV-infected mother-newborn pairs. The activation of the TLR7/8 pathway could function as an adjuvant to improve maternal-neonatal innate immunity.
    PLoS ONE 06/2013; 8(6):e67036. DOI:10.1371/journal.pone.0067036 · 3.23 Impact Factor
Show more