Abstract
HIV-1 trans-acting protein Tat, an essential protein for viral replication, is a key mediator of neurotoxicity. If Tat oxidant injury and neurotoxicity have been described, consequent neuroinflammation is less understood. Rat caudate-putamens (CPs) were challenged with Tat, with or without prior rSV40-delivered superoxide dismutase or glutathione peroxidase. Tat injection caused oxidative stress. Administration of Tat in the CP induced an increase in numbers of Iba-1- and CD68-positive cells, as well as an infiltration of astrocytes. We also tested the effect of more protracted Tat exposure on neuroinflammation using an experimental model of chronic Tat exposure. SV(Tat): a recombinant SV40-derived gene transfer vector was inoculated into the rat CP, leading to chronic expression of Tat, oxidative stress, and ongoing apoptosis, mainly located in neurons. Intra-CP SV(Tat) injection induced an increase in microglia and astrocytes, suggesting that protracted Tat production increased neuroinflammation. SV(SOD1) or SV(GPx1) significantly reduced neuroinflammation following Tat administration into the CP. Thus, Tat-induced oxidative stress, CNS injury, neuron loss and inflammation may be mitigated by antioxidant gene delivery.
Highlights
Under normal physiologic conditions, reactive oxygen species (ROS), which include superoxide (O2−), hydrogen peroxide (H2O2) and hydroxyl radical (OH−), are generated at low levels and play important roles in signaling and metabolic pathways [1]
Because oxidative injury is seen in the brains of patients with HIV-associated neurocognitive disorder (HAND), we tested for oxidative damage occurring after Tat injection
Our findings extend the principle of antioxidant protection from neuroinflammation to HIV-related injury, and suggest that rSV40 antioxidant gene delivery may be therapeutically applicable in the case of ongoing injury and neuroinflammation such as HAND
Summary
Reactive oxygen species (ROS), which include superoxide (O2−), hydrogen peroxide (H2O2) and hydroxyl radical (OH−), are generated at low levels and play important roles in signaling and metabolic pathways [1]. Oxidative stress arises due to the disturbances of the balance in pro-oxidant/antioxidant homeostasis that further causes the generation of ROS which are potentially toxic for neurons. Abnormalities in oxidative metabolism have been reported in many nervous system diseases. These include neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis and cerebellar degeneration) [2,3,4,5,6], vascular diseases (ischemia-reperfusion) [7] or toxic reactions (chronic alcoholism) [8], as well as aging [9]
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