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