Human immunodeficiency virus-1 env impairs Fc receptor-mediated phagocytosis via a cyclic adenosine monophosphate-dependent mechanism.
Human immunodeficiency virus (HIV)-1 expression in mononuclear phagocytes is associated with multiple functional defects, including phagocytosis. To assess Fcgamma receptor (FcgammaR) function in cells expressing HIV-1, human promonocytic cells (U937) acutely or chronically infected with HIV-1, or stably transfected with a noninfectious reverse transcriptase (RT) defective HIV-1 provirus (Deltapol), were treated with phorbol 12-myristate 13-acetate for 48 hours and tested for their ability to ingest sheep erythrocytes coated with IgG (E-IgG). HIV-1-infected or transfected U937 cells ingested 50% to 65% fewer E-IgG than controls despite normal surface expression of FcgammaRs. HIV-1 specifically impaired FcgammaR-mediated phagocytosis, as ingestion of complement-coated erythrocytes was unaffected. U937 cells transfected with an env deficient mutant of HIV-1 ingested E-IgG normally, suggesting that the expression of HIV-1 env was required for HIV-1 to inhibit FcgammaR-mediated phagocytosis. Expression of HIV-1 in U937 cells was associated with an increased accumulation of intracellular cyclic adenosine monophosphate (cAMP); addition of the adenylate cyclase inhibitor 2',5'-dideoxyadenosine to these cells decreased intracellular cAMP levels to that of controls and restored FcgammaR-mediated phagocytosis. Addition of either interferon (IFN)-gamma or an inhibitor of cAMP-dependent protein kinase A (KT 5720) to HIV-1-transfected U937 cells also restored FcgammaR-mediated phagocytosis. Expression of HIV-1 induces a specific defect of FcgammaR function in mononuclear phagocytes that correlates with increased levels of cAMP, and can be corrected by pharmacologic manipulation.
Thomas
C A
CA
Department of Physiology and Cellular Biophysics, Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA.
Weinberger
O K
OK
Ziegler
B L
BL
Greenberg
S
S
Schieren
I
I
Silverstein
S C
SC
El Khoury
J
J
D000242:Cyclic AMP / Q000276:immunology*; D015967:Gene Expression Regulation, Viral; D018014:Gene Transfer Techniques; D015752:Genes, env; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D015497:HIV-1; D006801:Humans; D009000:Monocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology; D010587:Phagocytosis / Q000235:genetics* / Q000276:immunology; D011961:Receptors, Fc / Q000276:immunology*; D014407:Tumor Cells, Cultured
D011961:Receptors, Fc; D000242:Cyclic AMP