REGULATION OF CYTOKINE EXPRESSION BY HIV

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Monocytes/macrophages play a critical role in the pathogenesis of human immunodeficiency virus (HIV) infection, both as targets viral replication and as sources of multifunctional cytokines. We have previously reported that the HIV-1 envelope glycoprotein, gp120, stimulates secretion of the potent vasoconstrictive peptide, endothelin-1 (ET-1), from human macrophages in a concentration- dependent manner. We also found that circulating monocytes in HIV-infected individuals express the ET-1 gene, while cells from healthy controls do not, and that cerebral macrophages in patients with HIV-encephalopathy are positive for ET-1. Thus, monocyte derived endothelins appear to be stimulated during HIV infection and their potent vasoactive properties could potentially mediate alterations in the cerebral perfusion pattern associated with AIDS dementia complex. Our recent studies looking at the effect of HIV infection on both constitutive and stimulated production of ET-1 by human macrophages suggest that infection with monocytropic HIV-1 isolates that are not neurotropic neither induces ET-1 nor potentiates its production by a known inducer, such as LPS. This analysis is being expanded to include macrophage tropic HIV isolates that are neurotropic to determine their influence on entry of HIV infected cells into the brain and , thus, their potential role in AIDS dementia. Inasmuch as AIDS is a disease characterized by a general dysregulation of cytokine production, we are also investigating the role of various cytokines in the regulation of ET-1 gene expression. We have found that the cytokine, interferon-gamma (IFN-g), is capable of inducing the expression of ET-1 in human monocytes/ macrophages in a concentration-dependent manner. Expression of the ET-1 gene in response to IFN-g occurs late compared to expression in response to inducers such as PMA, suggesting that induction of another cellular protein may precede the induction of ET-1. Investigations concerning potential mechanisms for the induction of ET-1 by IFN-g suggest a role for tumor necrosis factor alpha (TNF-a). Although TNF-a does not directly induce ET-1, it potentiates ET-1 production mediated by IFN-g. Furthermore, induction of ET-1 protein by IFN-g, but not PMA, can be blocked with soluble receptors for TNF. These findings will be used to investigate the mechanism of induction of ET-1 gene expression mediated by pathologic agents, such as bacterial LPS and the HIV envelope protein.