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Signaling Chain of FcR in Human Macrophages: A Possible Mechanism for Inhibition of Phagocytosis1
,
*
AIDS Pathogenesis Research Unit, Macfarlane Burnet Center,
National Center for HIV Virology Research; Departments of
Medicine and
Biochemistry, Monash University, and
¶ Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
HIV-1 infection impairs a number of macrophage effector functions,
thereby contributing to development of opportunistic infections and the
pathogenesis of AIDS. Fc
R-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 FcRs 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 FcRs, suggesting a
defect downstream of initial receptor activation. FcR-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
signaling subunit of FcR (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
signaling subunit augmented FcR-mediated phagocytosis, suggesting
that down-modulation of -chain protein expression in HIV-infected
MDM caused the defective FcR-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 FcR-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.
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