Conditional Human Immunodeficiency Virus Transactivator of Transcription Protein Expression Induces Depression-like Effects and Oxidative Stress

Abstract

BackgroundThe prevalence of major depression in people with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome is substantially higher than in the general population. Mechanisms underlying this comorbidity are poorly understood. HIV transactivator of transcription (Tat) protein, produced and excreted by HIV, could be involved. We determined whether conditional Tat protein expression in mice is sufficient to induce depression-like behaviors and oxidative stress. Further, as oxidative stress is associated with depression, we determined whether decreasing or increasing oxidative stress by administering methylsulfonylmethane (MSM) or diethylmaleate, respectively, altered depression-like behavior. MethodsGT-tg bigenic mice received intraperitoneal saline or doxycycline (25–100 mg/kg/day) to induce Tat expression. G-tg mice, which do not express Tat protein, also received doxycycline. Depression-like behavior was assessed with the tail suspension test and the two-bottle saccharin/water consumption task. Reactive oxygen species and reactive nitrogen species were assessed ex vivo. Medial frontal cortex oxidative stress and temperature were measured in vivo with 9.4T proton magnetic resonance spectroscopy. ResultsTat expression increased tail suspension test immobility time in an exposure-dependent manner and reduced saccharin consumption. MSM decreased immobility time, whereas diethylmaleate increased it in saline-treated GT-tg mice. Tat and MSM behavioral effects persisted for 28 days. Tat and diethylmaleate increased reactive oxygen species and reactive nitrogen species levels, whereas MSM decreased levels. Tat expression increased medial frontal cortex glutathione levels and temperature. ConclusionsTat expression induced rapid and enduring depression-like behaviors and oxidative stress. Increasing oxidative stress increased depression-like behavior, whereas decreasing oxidative stress decreased depression-like behavior. Thus, Tat produced by HIV may contribute to high depression prevalence among people with HIV. Mitigation of oxidative stress could reduce depression severity.