Nrf2-Mediated System xc- Activation in Astroglial Cells Is Involved in HIV-1 Tat-Induced Neurotoxicity

HIV-associated neurocognitive disorders (HANDs) affect a large part of HIV-infected patients, despite highly active antiretroviral therapy. HANDs occur in the absence of a direct infection of neurons. Nevertheless, viral proteins (e.g., Tat) are capable to cause neuronal dysfunction via oxidative stress, but the cellular pathways leading to HANDs are not yet fully defined. Here, we investigated the effects of Tat on Nrf2-mediated antioxidant response and system x(c)(-) expression in U373 human astroglial cells. Moreover, the effect of Tat-producing astrocytes on neuronal cell viability was assessed using SH-SY5Y cells as a culture model. We demonstrated that Tat produced by astrocytes was able to induce Nrf2 activation and system x(c)(-) expression in astrocytes, thus reducing cell viability of co-cultured neuronal cells. Furthermore, sulfasalazine, a specific system x(c)(-) inhibitor, was able to reduce extracellular glutamate and to prevent the reduction of neuronal viability, thus demonstrating that the neurotoxic effect was dependent on an increased glutamate release through the transporter. Our findings provide evidence of the involvement of astroglial Nrf2/system x(c)(-) pathway in the neurotoxicity induced by HIV-1 Tat protein, thereby suggesting how astrocytes may exacerbate neurodegeneration through the conversion of an antioxidant response to excitotoxicity.