Abstract
BackgroundMacrophages provide an interface between innate and adaptive immunity and are important long-lived reservoirs for Human Immunodeficiency Virus Type-1 (HIV-1). Multiple genetic networks involved in regulating signal transduction cascades and immune responses in macrophages are coordinately modulated by HIV-1 infection.Methodology/Principal FindingsTo evaluate complex interrelated processes and to assemble an integrated view of activated signaling networks, a systems biology strategy was applied to genomic and proteomic responses by primary human macrophages over the course of HIV-1 infection. Macrophage responses, including cell cycle, calcium, apoptosis, mitogen-activated protein kinases (MAPK), and cytokines/chemokines, to HIV-1 were temporally regulated, in the absence of cell proliferation. In contrast, Toll-like receptor (TLR) pathways remained unaltered by HIV-1, although TLRs 3, 4, 7, and 8 were expressed and responded to ligand stimulation in macrophages. HIV-1 failed to activate phosphorylation of IRAK-1 or IRF-3, modulate intracellular protein levels of Mx1, an interferon-stimulated gene, or stimulate secretion of TNF, IL-1β, or IL-6. Activation of pathways other than TLR was inadequate to stimulate, via cross-talk mechanisms through molecular hubs, the production of proinflammatory cytokines typical of a TLR response. HIV-1 sensitized macrophage responses to TLR ligands, and the magnitude of viral priming was related to virus replication.Conclusions/SignificanceHIV-1 induced a primed, proinflammatory state, M1HIV, which increased the responsiveness of macrophages to TLR ligands. HIV-1 might passively evade pattern recognition, actively inhibit or suppress recognition and signaling, or require dynamic interactions between macrophages and other cells, such as lymphocytes or endothelial cells. HIV-1 evasion of TLR recognition and simultaneous priming of macrophages may represent a strategy for viral survival, contribute to immune pathogenesis, and provide important targets for therapeutic approaches.
Highlights
Tissue macrophages play a central role in immune response pathways and are major targets for chronic infection by viruses including Human Immunodeficiency Virus Type-1 (HIV-1)
HIV-1 genomic RNA activates plasmacytoid dendritic cells and monocytes through pattern recognition receptors, Tolllike receptor-7 (TLR7), which initiate a signal transduction cascade to mediate release of tumor necrosis factor (TNF) and interferons [18,19] that may contribute to viral replication [20]
HIV-1 treatment of macrophages stimulates a temporal program of gene expression
Summary
Tissue macrophages play a central role in immune response pathways and are major targets for chronic infection by viruses including HIV-1. Infected macrophages constitute a stable viral reservoir that facilitate spread of HIV-1 to other cells or tissue compartments and contribute to immune pathogenesis [1,2,3,4,5,6,7]. HIV-1 genomic RNA activates plasmacytoid dendritic cells (pDC) and monocytes through pattern recognition receptors, Tolllike receptor-7 (TLR7), which initiate a signal transduction cascade to mediate release of TNF and interferons [18,19] that may contribute to viral replication [20]. Multiple genetic networks involved in regulating signal transduction cascades and immune responses in macrophages are coordinately modulated by HIV-1 infection
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