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Human Immunodeficiency Virus-1 env Impairs Fc Receptor-Mediated Phagocytosis Via a Cyclic Adenosine Monophosphate-Dependent Mechanism
Christian A. Thomas,
Ofra K. Weinberger,
Benedikt L. Ziegler,
Steven Greenberg,
Ira Schieren,
Samuel C. Silverstein, and
Joseph El Khoury
From the Departments of Physiology and Cellular Biophysics, Medicine, and The Howard Hughes Medical Institute, Columbia University, New York; the Department of Medicine, Beth Israel Medical Center, Albert Einstein College of Medicine, New York, NY; and the Department of Hematology and Oncology, University of Tübingen, Tübingen, Germany.
Human immunodeficiency virus (HIV)-1 expression in mononuclear phagocytes is associated with multiple functional defects, including phagocytosis. To assess Fc receptor (FcR) 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 ( pol), 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 FcRs. HIV-1 specifically impaired FcR-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 FcR-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 FcR-mediated phagocytosis. Addition of either interferon (IFN)- or an inhibitor of cAMP-dependent protein kinase A (KT 5720) to HIV-1-transfected U937 cells also restored FcR-mediated phagocytosis. Expression of HIV-1 induces a specific defect of FcR function in mononuclear phagocytes that correlates with increased levels of cAMP, and can be corrected by pharmacologic manipulation.
Blood, Vol. 90 No. 9 (November 1), 1997:
pp. 3760-3765
© 1997 by The American Society of Hematology.
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