Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands

Partners AIDS Research Center, Massachusetts General Hospital, Division of AIDS, Harvard Medical School, Boston, Massachusetts, USA.
AIDS (London, England) (Impact Factor: 5.55). 04/2008; 22(5):655-8. DOI: 10.1097/QAD.0b013e3282f4de23
Source: PubMed


Increased PD-L1 expression has been reported in HIV-1-infected individuals, but the mechanisms leading to PD-L1 upregulation remain to be elucidated. Here we demonstrate that HIV-1-derived Toll-like receptor (TLR)7/8 ligands can induce MyD88-dependent upregulation of PD-L1 on plasmacytoid dendritic cells, myeloidic dendritic cells and monocytes. These data suggest a mechanism through which HIV-1-derived TLR ligands might contribute to the functional impairment of virus-specific PD-1-positive T cells by inducing the upregulation of PD-L1 on antigen-presenting cells.

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Available from: Mark Brockman, Mar 22, 2014
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    • "Studies comparing NH and NNH have corroborated the hypothesis that hyperactive innate immune responses contribute to pathogenesis, as both NH and NNH express robust levels of ISGs during acute infection in vivo [5]–[7], but NH control this response within weeks while levels of IFNα mRNA and ISGs remain elevated in NNH throughout chronic infection [5]–[9]. These ISGs include TRAIL and Fas ligand (FasL), which can induce apoptosis of uninfected CD4+ T cells expressing the cognate receptors death receptor 5 (DR5) and Fas, and programmed death ligand 1 (PDL1), which can induce apoptosis or exhaustion of CD8+ T cells expressing the corresponding receptor programmed cell death 1 (PD1) [27]–[30]. Thus, despite the need for an early phase of IFN expression to stimulate adaptive immune responses and assist in the control of virus replication, chronic expression of type I IFN and ISGs likely does more harm than good in HIV/SIV infection of NNH [31]. "
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    ABSTRACT: HIV immune pathogenesis is postulated to involve two major mechanisms: 1) chronic innate immune responses that drive T cell activation and apoptosis and 2) induction of immune regulators that suppress T cell function and proliferation. Both arms are elevated chronically in lymphoid tissues of non-natural hosts, which ultimately develop AIDS. However, these mechanisms are not elevated chronically in natural hosts of SIV infection that avert immune pathogenesis despite similarly high viral loads. In this study we investigated whether minocycline could modulate these pathogenic antiviral responses in non-natural hosts of HIV and SIV. We found that minocycline attenuated in vitro induction of type I interferon (IFN) and the IFN-stimulated genes indoleamine 2,3-dioxygenase (IDO1) and TNF-related apoptosis inducing ligand (TRAIL) in human plasmacytoid dendritic cells and PBMCs exposed to aldrithiol-2 inactivated HIV or infectious influenza virus. Activation-induced TRAIL and expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in isolated CD4+ T cells were also reduced by minocycline. Translation of these in vitro findings to in vivo effects, however, were mixed as minocycline significantly reduced markers of activation and activation-induced cell death (CD25, Fas, caspase-3) but did not affect expression of IFNβ or the IFN-stimulated genes IDO1, FasL, or Mx in the spleens of chronically SIV-infected pigtailed macaques. TRAIL expression, reflecting the mixed effects of minocycline on activation and type I IFN stimuli, was reduced by half, but this change was not significant. These results show that minocycline administered after infection may protect against aspects of activation-induced cell death during HIV/SIV immune disease, but that in vitro effects of minocycline on type I IFN responses are not recapitulated in a rapid progressor model in vivo.
    PLoS ONE 04/2014; 9(4):e94375. DOI:10.1371/journal.pone.0094375 · 3.23 Impact Factor
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    • "PD1 is known to inhibit naive T-cell activation [33] and PD1 expression is increased on HIV specific T-cells [34]. The ligand for PD1, PD-L1, has been shown to be expressed at increased levels on MDC, CD14+, and CD19+ cells from HIV+ subjects, and expression is related to markers of HIV disease stage [32], [35] At the same time, TLR ligands derived from HIV directly upregulate PD-L1 on DC and monocytes in vitro [36]. We therefore investigated expression of PD-L1, along with other inhibitory receptors PDL-2 and ILT3 [37], [38], [39]. "
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    ABSTRACT: HIV infection is characterized by ineffective anti-viral T-cell responses and impaired dendritic cell (DC) functions, including response to Toll-Like Receptor (TLR) ligands. Because TLR responsiveness may affect a host's response to virus, we examined TLR ligand induced Myeloid and Plasmacytoid DC (MDC and PDC) activation of naïve T-cells in HIV+ subjects. Freshly purified MDC and PDC obtained from HIV+ subjects and healthy controls were cultured in the presence and absence of TLR ligands (poly I∶C or R-848). We evaluated indices of maturation/activation (CD83, CD86, and HLA-DR expression), cytokine secretion (IFN-alpha and IL-6), and ability to activate allogeneic naïve CD4 T-cells to secrete IFN-gamma and IL-2. MDC from HIV+ subjects had increased spontaneous IL-6 production and increased CD83 and CD86 expression when compared to MDC of controls. MDC IL-6 expression was associated with plasma HIV level. At the same time, poly I∶C induced HLA-DR up-regulation on MDC was reduced in HIV+ persons when compared to controls. The latter finding was associated with impaired ability of MDC from HIV+ subjects to activate allogeneic naïve CD4 T-cells. PDC from HIV+ persons had increased spontaneous and TLR ligand induced IL-6 expression, and increased HLA-DR expression at baseline. The latter was associated with an intact ability of HIV PDC to activate allogeneic naïve CD4 T-cells. These results have implications for the ability of the HIV+ host to form innate and adaptive responses to HIV and other pathogens.
    PLoS ONE 09/2011; 6(9):e23884. DOI:10.1371/journal.pone.0023884 · 3.23 Impact Factor
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    • "Monocytes and CCR5 + T cells from HIV-uninfected persons up-regulate PD-L1, but not PD- L2, upon in vitro exposure to HIV, through a mechanism involving IFN-[322]. Another mechanism for the increased expression of PD-L1 during HIV infection could be the presence of HIV-derived TLR 7/8 ligands [323]. CD14 + cells and mDCs in the lymph "
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    ABSTRACT: HIV infection is characterized by a number of abnormalities in several components of the immune system. For example, during HIV infection, a massive decrease of CD4(+) T cells is observed, as well as a progressive depletion of naïve CD8(+) T cells. Furthermore, elevated numbers of apoptotic B and T cells are present in HIV-infected patients, and a systemic immune activation results in T-cell exhaustion. Finally, HIV infection is characterized by the presence of functionally impaired dendritic cells, with decreased expression of maturation markers, decreased secretion of cytokines and defects in antigen processing and presentation. All these characteristics result in the occurrence of non-functional cytotoxic T lymphocytes, that fail to control HIV-replication in most individuals during progressive disease. Costimulatory and co-inhibitory molecules are involved in the activation, differentiation and survival of several cell-types of the immune system. Each costimulatory receptor (generally expressed on effector cells) can conjugate with one or more specific ligands (expressed on antigen-presenting cells), which leads to an activation of intracellular signaling pathways inside the cells on which they are expressed. HIV infection is characterized by an aberrant expression of these molecules on cells of the immune system. Many of the immune deficiencies mentioned in the previous paragraph can be explained by abnormal expression of costimulatory molecules, and could consequently be overcome by interfering with their interactions. In this review, we give an overview of the functions and expression patterns of the receptor/ligand pairs of the tumor necrosis factor and the B7 super-families of costimulatory and co-inhibitory molecules in HIV-infected patients. We will also discuss possibilities for manipulating their signaling as a therapeutic anti-HIV tool.
    Current Molecular Medicine 03/2011; 11(3):172-96. DOI:10.2174/1566211213754945240 · 3.62 Impact Factor
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