title: HIV-1 activates macrophages independent of Toll-like receptors.
abstract: BACKGROUND
  Macrophages 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.
  
  
  RESULTS
  To 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-1beta, 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
  HIV-1 induced a primed, proinflammatory state, M1(HIV), 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.
authors.affiliation: Division of Rheumatology, Immunology and Infectious Diseases, Department of Pathology, Immunology, and Laboratory Medicine, and Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Brown
authors.forename: James J
authors.initials: JJ
authors.lastname: Kohler
authors.forename: Carter R
authors.initials: CR
authors.lastname: Coberley
authors.forename: John W
authors.initials: JW
authors.lastname: Sleasman
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Goodenow
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism* / Q000821:virology*; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*
chemical_list: D051193:Toll-Like Receptors