CHRONIC ALCOHOL-INTOXICATION ATTENUATES HUMAN IMMUNODEFICIENCY VIRUS-1 GLYCOPROTEIN 120-INDUCED SUPEROXIDE ANION RELEASE BY ISOLATED KUPFFER CELLS

This work tests the hypothesis that chronic alcohol intoxication suppr esses the microbicidal activity of Kupffer cells by modulating the exp ression of cell surface receptors associated with respiratory burst an d the release of potent microbicidal agents [i.e., reactive oxygen spe cies (ROS)]. Because alcohol is also a potential risk factor in human immunodeficiency virus-1 (HIV-1) infection, this study examines the ef fect of HIV-1 glycoprotein 120 (gp120)-induced ROS release by isolated Kupffer cells. After 16 weeks of ethanol feeding, Kupffer cells from male Sprague-Dawley rats were isolated and assayed for HIV-1 gp120-ind uced superoxide release, Fluorescein isothiocyanate (FITC)-HIV-1 gp120 binding, NADPH oxidase, and protein kinase C activity in Kupffer cell s were measured. Results show that HIV-1 gp120 induced the release of superoxide anion in a dose-dependent manner in normal rats. Mannosylat ed-bovine serum albumin inhibited FITC-HIV-1 gp120-mediaied superoxide release in normal Kupffer cells by 85%. Moreover, 83 +/- 6% of Kupffe r cells were FITC-HIV 1 gp120-positive, whereas <30% were CD4-positive . In alcohol-fed rats, HIV-1 gp120-induced ROS release was reduced by 70% and FITC-HIV-1 gp120 binding (in terms of fluorescence intensity p er 10(6) Kupffer cells) by 44% in Kupffer cells, without any change in percent positive cells for this ligand. Concomitantly, HLV-1 gp120-in duced translocation of NADPH oxidase to the plasma membranes of Kupffe r cells in alcohol-fed rats was suppressed by 60%, In contrast, alcoho l consumption significantly increased total protein kinase C activity and phorbol ester-induced superoxide release by Kupffer cells. These s tudies demonstrate that Kupffer cells are likely targets of HIV-1 whos e binding sites on macrophages could also include mannose-specific rec eptors, These observations further suggest that suppression of HIV-1 g p120-mediated ROS production in chronic alcoholics is due to altered c ell surface receptor expression for gp120, and defective postreceptor signaling mechanisms, which in turn could lead to attenuated microbici dal activity of hepatic macrophages.