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 associated 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 proteins, such as Tat, can modulate the activity of the inducible nitric oxide synthase (iNos) gene when expressed in stable transfectant lines of RAW264.7 cells. A bioassay for Tat, based on transactivation of an HIV-1 LTR-CAT reporter gene, allowed selection of Tat-expressing cells. Parental and Tat-expressing macrophages accumulated identical levels of nitrite following lipopolysaccharide (LPS) stimulation. Interferon γ (IFN-γ) stimulation however, resulted in reduced levels of nitrite accumulation as a direct consequence of Tat expression. Conditioned media from Tat-expressing cells reduced the level of nitrite accumulation in parental cells following IFN-γ stimulation but not stimulation with LPS. These results implicate HIV-1 Tat as a modulator of the IFN-γ-specific signal transduction pathways leading to iNos expression.