Prostaglandin E2 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. PGE2 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. (C) 2002 Elsevier Science (USA). All rights reserved.