HIV-1 Down-Modulates γ Signaling Chain of FcγR 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. FcγR-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 FcγRs 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 FcγRs, suggesting a defect downstream of initial receptor activation. FcγR-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 γ signaling subunit of FcγR (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 γ signaling subunit augmented FcγR-mediated phagocytosis, suggesting that down-modulation of γ-chain protein expression in HIV-infected MDM caused the defective FcγR-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 FcγR-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.

RON Receptor Tyrosine Kinase, a Negative Regulator of Inflammation, Inhibits HIV-1 Transcription in Monocytes/Macrophages and Is Decreased in Brain Tissue from Patients with AIDS

“…Critical regulators of inflammation include Fc␥R, phosphatidylserine receptor, and the Tyro 3 family of receptors (56 -59). HIV-1 has been associated with a decrease in the expression of Fc␥Rs (60) and inhibition of Fc-mediated phagocytosis (61). Our data suggest that RON receptor tyrosine kinase, which has also been shown to negatively regulate inflammation and macrophage function (20), inhibits HIV-1 expression and may be a target of HIV-1 infection.…”

Involvement of FcγR I (CD64) in the Mechanism of HIV-1 Inhibition by Polyclonal IgG Purified from Infected Patients in Cultured Monocyte-Derived Macrophages

“…Indeed, after in vitro infection with HIV-1 BaL , phagocytosis of immune complexes mediated by both Fc␥R and complement receptors is impaired in human-infected MDM (45). These authors have shown that infection of macrophages by HIV did not affect surface expression of either Fc␥R or the major complement receptor, but in HIV-infected macrophages signal transduction is decreased and clearance of IgG-opsonized targets via Fc␥R is altered.…”

Macrophages and HIV-1: dangerous liaisons

“…Monocyte/macrophage functions that are essential for adequate innate and adaptive responses to pathogens, such as antigen presentation, intracellular pathogen killing or phagocytosis, are affected by HIV-1 infection (Biggs et al, 1995;Kumar et al, 1999;Polyak et al, 1997;Yoo et al, 1996); revewed in (Kedzierska et al, 2003a). Phagocytosis is mediated by a number of phagocytic receptors expressed on monocytes/macrophages, including complement receptors (CR) and receptors for the Fc portion of immunoglobulins (FcR) (Aderem and Underhill, 1999) (Kedzierska et al, 2002).…”

“…This defect was attributed to the down-regulation of the intracytoplasmic expression of the  signalling subunit, probably at the posttranscriptional level (Kedzierska et al, 2002). FcRIIA and FcRIII on macrophage surface by specific Fab or (Fab') 2 cross-linking also inhibits HIV-1 replication .…”