POTENT STIMULATION OF MONOCYTIC ENDOTHELIN-1 PRODUCTION BY HIV-1 GLYCOPROTEIN-120

Monocytes/macrophages play a critical role in the pathogenesis of HIV infection, both as targets for virus replication and as sources of pro duction of multifunctional cytokines. Endothelins, peptides with poten t vasoconstricting activities originally isolated from endothelial cel ls, are also produced and secreted by macrophages in a manner similar to that of other cytokines. In an attempt to explore the potential rol e of endothelins in HIV-infection, we investigated the effect of the H IV-1 envelope glycoprotein, glycoprotein 120, on monocytic endothelin- 1 production. This glycoprotein has been identified as a potent stimul ator of monokines such as TNF-alpha and IL-6, which have been implicat ed as potential mediators of HIV-encephalopathy. We found that glycopr otein 120, similar to LPS, stimulates the secretion of endothelin-1, a s well as TNF-alpha, from macrophages in a concentration-dependent man ner. Using reverse transcriptase polymerase chain reaction, we found t hat circulating monocytes in HIV-infected individuals show a distinct expression of the endothelin-1 gene that is not detectable in healthy controls, indicating chronic activation of this gene in HIV-infection. In addition, cerebral macrophages in patients with HIV-encephalopathy were strongly positive for endothelin. Thus, monocytic endothelins ap pear to be stimulated during HIV infection. Their potent vasoactive pr operties render them potential candidates for mediating alterations in the cerebral perfusion pattern associated with the AIDS dementia comp lex.