THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REGULATORY PROTEIN TAT INHIBITS INTERFERON-INDUCED INOS ACTIVITY IN A MURINE MACROPHAGE CELL-LINE

Human immunodeficiency virus type 1 (HIV-1) infection is frequently as sociated with concurrent infection by opportunistic pathogens, against which production of nitric oxide by host macrophages provides a first line of defence. We have investigated whether regulatory HIV-1 protei ns, such as Tat, can modulate the activity of the inducible nitric oxi de synthase (iNos) gene when expressed in stable transfectant lines of RAW264.7 cells. A bioassay for Tat, based on transactivation of an HI V-1 LTR-CAT reporter gene, allowed selection of Tat-expressing cells. Parental and Tat-expressing macrophages accumulated identical levels o f nitrite following lipopolysaccharide (LPS) stimulation. Interferon g amma (IFN-gamma) stimulation however, resulted in reduced levels of ni trite accumulation as a direct consequence of Tat expression. Conditio ned media from Tat-expressing cells reduced the level of nitrite accum ulation in parental cells following IFN-gamma stimulation but not stim ulation with LPS, These results implicate HIV-1 Tat as a modulator of the IFN-gamma-specific signal transduction pathways leading to iNos ex pression.