Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice

Human immunodeficiency virus (HIV) progressively depletes GSH content in hu mans. Although the accumulated evidence suggests a role of decreased GSH in the pathogenesis of HIV, significant controversy remains concerning the me chanism of GSH depletion, especially in regard to envisioning appropriate t herapeutic strategies to help compensate for such decreased antioxidant cap acity. Tat, a transactivator encoded by HIV, is sufficient to cause GSH dep letion in vitro and is implicated in AIDS-associated Kaposi's sarcoma and B cell lymphoma. In this study, we report a decrease in GSH biosynthesis wit h Tat, using HIV-1 Tat transgenic (Tat+) mice. A significant decline in the total intracellular GSH content in liver and erythrocytes of Tat+ mice was accompanied by decreased gamma-glutamylcysteine synthetase regulatory subu nit mRNA and protein content, which resulted in an increased sensitivity of gamma-glutamylcysteine synthetase to feedback inhibition by GSH, Further s tudy revealed a significant reduction in the activity of GSH synthetase in liver of Tat+ mice, which was linearly associated with their GSH content. T herefore, Tat appears to decrease GSH in vivo, at least partially, through modulation of GSH biosynthetic enzymes.