title: Impaired complement-mediated phagocytosis by HIV type-1-infected human monocyte-derived macrophages involves a cAMP-dependent mechanism.
abstract: HIV-1 infection of cells of macrophage lineage impairs a number of effector functions performed by these cells, including phagocytosis of opsonized pathogens. In this study we investigate the effects of HIV-1 on the mechanism of complement (C')-mediated phagocytosis by human monocyte-derived macrophages (MDM). Using C'-opsonized sheep red blood cells (sRBC) as targets, we demonstrate that phagocytosis is inhibited by HIV-1 infection in vitro. Inhibition is not due to downregulation of surface C' receptors (R) or altered binding of C'-opsonized targets to HIV-1-infected MDM, suggesting a postreceptor-mediated mechanism of suppression. Having shown that increased levels of intracellular cAMP in uninfected MDM inhibit phagocytosis, we demonstrate that HIV-1 infection of MDM is associated with increased intracellular cAMP. Using the adenylate cyclase inhibitors 2',5'-dideoxyadenosine and MDL-12,330A, we show that phagocytosis by HIV-1- infected MDM can be restored by inhibition of cAMP production. Defective phagocytosis by HIV-1-infected MDM did not correlate with prostaglandin secretion, and was less in uninfected MDM within the HIV-1-infected cell culture suggesting a minimal bystander effect. Inhibition required viral entry but not active viral replication, as shown by use of the antiretroviral drug lamivudine. Hence, our study suggests that HIV-1 impairs C'R-mediated phagocytosis in MDM by elevating intracellular cAMP levels, independent of prostaglandin secretion, and contributes to our understanding of how HIV-1 impairs cell-mediated immunity.
authors.affiliation: AIDS Pathogenesis and Clinical Research Program, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Australia.
authors.forename: Rula
authors.initials: R
authors.lastname: Azzam
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
authors.forename: Edwin
authors.initials: E
authors.lastname: Leeansyah
authors.forename: Hiutat
authors.initials: H
authors.lastname: Chan
authors.forename: Daniel
authors.initials: D
authors.lastname: Doischer
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Cunningham
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Crowe
authors.forename: Anthony
authors.initials: A
authors.lastname: Jaworowski
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004912:Erythrocytes; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007097:Imines / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D010587:Phagocytosis / Q000276:immunology*; D011951:Receptors, Complement / Q000276:immunology* / Q000378:metabolism; D012756:Sheep; D014779:Virus Replication
chemical_list: D007097:Imines; D011951:Receptors, Complement; D016048:Dideoxyadenosine; C014925:RMI 12330A; C021008:2',5'-dideoxyadenosine; D000242:Cyclic AMP; D015232:Dinoprostone