title: HIV-1 down-modulates gamma signaling chain of Fc gamma R in human macrophages: a possible mechanism for inhibition of phagocytosis.
abstract: HIV-1 infection impairs a number of macrophage effector functions, thereby contributing to development of opportunistic infections and the pathogenesis of AIDS. FcgammaR-mediated phagocytosis by human monocyte-derived macrophages (MDM) is inhibited by HIV-1 infection in vitro, and the underlying mechanism was investigated in this study. Inhibition of phagocytosis directly correlated with the multiplicity of HIV-1 infection. Expression of surface FcgammaRs was unaffected by HIV-1 infection, suggesting that inhibition of phagocytosis occurred during or after receptor binding. HIV-1 infection of MDM markedly inhibited tyrosine phosphorylation of the cellular proteins, which occurs following engagement of FcgammaRs, suggesting a defect downstream of initial receptor activation. FcgammaR-mediated phagocytosis in HIV-infected MDM was associated with inhibition of phosphorylation of tyrosine kinases from two different families, Hck and Syk, defective formation of Syk complexes with other tyrosine-phosphorylated proteins, and inhibition of paxillin activation. Down-modulation of protein expression but not mRNA of the gamma signaling subunit of FcgammaR (a docking site for Syk) was observed in HIV-infected MDM. Infection of MDM with a construct of HIV-1 in which nef was replaced with the gene for the gamma signaling subunit augmented FcgammaR-mediated phagocytosis, suggesting that down-modulation of gamma-chain protein expression in HIV-infected MDM caused the defective FcgammaR-mediated signaling and impairment of phagocytosis. This study is the first to demonstrate a specific alteration in phagocytosis signal transduction pathway, which provides a mechanism for the observed impaired FcgammaR-mediated phagocytosis in HIV-infected macrophages and contributes to the understanding of how HIV-1 impairs cell-mediated immunity leading to HIV-1 disease progression.
authors.affiliation: AIDS Pathogenesis Research Unit, Macfarlane Burnet Center, Victoria, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
authors.forename: Philip
authors.initials: P
authors.lastname: Ellery
authors.forename: Johnson
authors.initials: J
authors.lastname: Mak
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Crowe
authors.forename: Anthony
authors.initials: A
authors.lastname: Jaworowski
mesh_terms: D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051419:Paxillin; D010587:Phagocytosis / Q000276:immunology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051572:Proto-Oncogene Proteins c-hck; D017452:Receptors, IgG / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase; D014443:Tyrosine / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; D014443:Tyrosine; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck; C000606896:SYK protein, human; D000072377:Syk Kinase