PROSTAGLANDIN E-2 INDUCES RESISTANCE TO HUMAN IMMUNODEFICIENCY VIRUS-1 INFECTION IN MONOCYTE-DERIVED MACROPHAGES - DOWN-REGULATION OF CCR5 EXPRESSION BY CYCLIC ADENOSINE-MONOPHOSPHATE

The chemokine receptor CCR5 can function as a coreceptor for human imm unodeficiency virus-1 (HIV-1) entry into CD4(+) T cells and macrophage s, especially during the early stages of HIV-1 infection. The regulati on of CCR5 expression may affect not only leukocyte migration, but als o infectivity by HIV-1 and, therefore, acquired immunodeficiency syndr ome (AIDS) pathogenesis. We report here that agents which increase int racellular concentrations of cyclic adenosine monophosphate (cAMP) rap idly downregulate CCR5 gene expression, with consequent loss of CCR5 e xpression and function in monocytes/macrophages. Chemotaxis and intra cellular Ca2+ mobilization in monocytes pretreated with prostaglandin E-2 or dibutyryl cAMP for 24 hours were significantly reduced in respo nse to the CCR5 ligand, MIP-1 beta, Moreover, HIV-1 entry into monocyt e-derived macrophages pretreated with dibutyryl-cAMP or prostaglandin E-2 was markedly decreased. Our findings suggest that resistance to HI V-1 can be induced by agents which increase cellular levels of cAMP an d that this may suggest additional therapeutic strategies to limit inf ection by HIV-1. (C) 1998 by The American Society of Hematology.