title: The mechanism underlying defective Fcgamma receptor-mediated phagocytosis by HIV-1-infected human monocyte-derived macrophages.
abstract: Clearance of IgG-opsonized erythrocytes is impaired in HIV-1-infected patients, suggesting defective FcgammaR-mediated phagocytosis in vivo. We have previously shown defective FcgammaR-mediated phagocytosis in HIV-1-infected human monocyte-derived macrophages (MDM), establishing an in vitro model for defective tissue macrophages. Inhibition was associated with decreased protein expression of FcR gamma-chain, which transduces immune receptor signals via ITAM motifs. FcgammaRI and FcgammaRIIIa signal via gamma-chain, whereas FcgammaRIIa does not. In this study, we showed that HIV-1 infection inhibited FcgammaRI-, but not FcgammaRIIa-dependent Syk activation in MDM, showing that inhibition was specific for gamma-chain-dependent signaling. HIV-1 infection did not impair gamma-chain mRNA levels measured by real-time PCR, suggesting a posttranscriptional mechanism of gamma-chain depletion. HIV-1 infection did not affect gamma-chain degradation (n = 7, p = 0.94) measured in metabolic labeling/chase experiments, whereas gamma-chain biosynthesis was inhibited (n = 12, p = 0.0068). Using an enhanced GFP-expressing HIV-1 strain, we showed that FcgammaR-mediated phagocytosis inhibition is predominantly due to a bystander effect. Experiments in which MDM were infected in the presence of the antiretroviral drug 3TC suggest that active viral replication is required for inhibition of phagocytosis in MDM. These data suggest that HIV-1 infection may affect only gamma-chain-dependent FcgammaR functions, but that this is not restricted to HIV-1-infected cells.
authors.affiliation: AIDS Pathogenesis and Clinical Research Program, The Macfarlane Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, Australia 3004.
authors.forename: Edwin
authors.initials: E
authors.lastname: Leeansyah
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Wines
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Crowe
authors.forename: Anthony
authors.initials: A
authors.lastname: Jaworowski
mesh_terms: D024201:Bystander Effect / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D014158:Transcription, Genetic / Q000235:genetics; D014779:Virus Replication
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase