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The Mechanism Underlying Defective Fc Receptor-Mediated Phagocytosis by HIV-1-Infected Human Monocyte-Derived Macrophages¹

Edwin Leeansyah^*,, Bruce D. Wines, Suzanne M. Crowe^*, and Anthony Jaworowski^2,*,

^* AIDS Pathogenesis and Clinical Research Program, The Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia; Helen Macpherson Smith Inflammatory Diseases Laboratory, The Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia; and Department of Medicine, Monash University, Melbourne, Australia

Clearance of IgG-opsonized erythrocytes is impaired in HIV-1-infected patients, suggesting defective FcR-mediated phagocytosis in vivo. We have previously shown defective FcR-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 -chain, which transduces immune receptor signals via ITAM motifs. FcRI and FcRIIIa signal via -chain, whereas FcRIIa does not. In this study, we showed that HIV-1 infection inhibited FcRI-, but not FcRIIa-dependent Syk activation in MDM, showing that inhibition was specific for -chain-dependent signaling. HIV-1 infection did not impair -chain mRNA levels measured by real-time PCR, suggesting a posttranscriptional mechanism of -chain depletion. HIV-1 infection did not affect -chain degradation (n = 7, p = 0.94) measured in metabolic labeling/chase experiments, whereas -chain biosynthesis was inhibited (n = 12, p = 0.0068). Using an enhanced GFP-expressing HIV-1 strain, we showed that FcR-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 -chain-dependent FcR functions, but that this is not restricted to HIV-1-infected cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Health and Medical Research Council Program Grant 358399. E.L. is a recipient of an Australian postgraduate award, and S.M.C. of a National Health and Medical Research Council Principal Research Fellowship.

² Address correspondence and reprint requests to Dr. Anthony Jaworowski, AIDS Pathogenesis and Clinical Research Program, The Macfarlane Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, Victoria, Australia 3004. E-mail address: anthonyj{at}burnet.edu.au

³ Abbreviations used in this paper: MDM, monocyte-derived macrophage; Ct, comparative threshold; EGFP, enhanced GFP; RT, reverse transcriptase; TLB, Triton lysis buffer.

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