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HIV-1 down-modulates γ signaling chain of FcγR in human macrophages : a possible mechanism for inhibition of phagocytosis

Kedzierska, Katherine, Ellery, Philip, Mak, Johnson, Lewin, Sharon R., Crowe, Suzanne M. and Jaworowski, Anthony 2002, HIV-1 down-modulates γ signaling chain of FcγR in human macrophages : a possible mechanism for inhibition of phagocytosis, Journal of immunology, vol. 168, no. 6, pp. 2895-2903.

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Title HIV-1 down-modulates γ signaling chain of FcγR in human macrophages : a possible mechanism for inhibition of phagocytosis
Author(s) Kedzierska, Katherine
Ellery, Philip
Mak, JohnsonORCID iD for Mak, Johnson orcid.org/0000-0002-5229-5707
Lewin, Sharon R.
Crowe, Suzanne M.
Jaworowski, Anthony
Journal name Journal of immunology
Volume number 168
Issue number 6
Start page 2895
End page 2903
Total pages 9
Publisher American Association of Immunologists
Place of publication Bethesda, Md.
Publication date 2002-03-15
ISSN 0022-1767
1550-6606
Keyword(s) cultured cells
cyclic AMP
cytoskeletal proteins
down-regulation
enzyme precursors
HIV infections
HIV-1
intracellular signaling peptides and proteins
macrophages
monocytes
paxillin
phagocytosis
phosphoproteins
phosphorylation
Summary 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.
Language eng
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2002, The American Association of Immunologists
Persistent URL http://hdl.handle.net/10536/DRO/DU:30047513

Document type: Journal Article
Collection: School of Medicine
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