Prostaglandin E(2) inhibits replication of HIV-1 in macrophages through activation of protein kinase A.
Since macrophages are a source of increased PGE(2) in AIDS, we investigated the role of PGE(2) in the replication of HIV-1 in these cells. PGE(2) inhibited HIV-1 replication measured by reverse transcriptase in human monocyte-derived macrophage (MDM). Treatment of MDM with the PGE(1) analog misoprostol, the adenylate cyclase activator forskolin, and the cyclic AMP analog dibutyryl-cyclic AMP (db-cAMP) suppressed HIV replication. The protein kinase A (PKA) activator 8-bromo-cyclic AMP also inhibited HIV-1 replication. Similar results were observed with the entry-independent, latently HIV-infected U1 cells. There was a parallel decrease in HIV-1 mRNA levels following PGE(2) treatment. Co-transfection of the HIV-1 promoter LTR.luciferase, with the vector CMV.Calpha, which expresses the PKA catalytic unit increasing PKA activity, reduced HIV-1 promoter activity. Inhibition of PKA activity with the pMT.RAB vector, a mutant regulatory unit of PKA, augmented HIV-1 promoter activity. In summary, PGE(2) inhibits HIV-1 gene expression in MDM through a PKA-dependent mechanism.
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor 48109, USA.
Michael M
MM
Hayes
Brian R
BR
Lane
Steven R
SR
King
David M
DM
Markovitz
Michael J
MJ
Coffey
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000821:virology*; D016595:Misoprostol / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology; D011401:Promoter Regions, Genetic; D012367:RNA, Viral / Q000096:biosynthesis; D019713:Receptors, CCR5 / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D019713:Receptors, CCR5; D016595:Misoprostol; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003994:Bucladesine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone