Human Immunodeficiency Virus-1 env Impairs Fcγ Receptor-Mediated Phagocytosis Via a Cyclic Adenosine Monophosphate-Dependent Mechanism

Abstract

AbstractHuman immunodeficiency virus (HIV)-1 expression in mononuclear phagocytes is associated with multiple functional defects, including phagocytosis. To assess Fcγ receptor (FcγR) 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 (Δpol), 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 FcγRs. HIV-1 specifically impaired FcγR-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 FcγR-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 FcγR-mediated phagocytosis. Addition of either interferon (IFN)-γ or an inhibitor of cAMP-dependent protein kinase A (KT 5720) to HIV-1–transfected U937 cells also restored FcγR-mediated phagocytosis. Expression of HIV-1 induces a specific defect of FcγR function in mononuclear phagocytes that correlates with increased levels of cAMP, and can be corrected by pharmacologic manipulation.