Calcium flux and neuronal cell death induced by the HIV-1 proteins Tat and gp120 (Immune deficiency).

摘要

AIDS-related cognitive-motor complex is a dementing illness that is a pathophysiological consequence of HIV-1 disease; it is characterized by deficits in cognition, behavior and motor function. Although, neurons are not themselves infected by HIV-1, the selective loss of neurons in brain almost certainly contributes to AIDS-dementia. Viral proteins including gp120, Tat, Vpu and Nef can be toxic to neurons. The HIV-1 coat glycoprotein, gp120, and the viral trans-activator, Tat, are, at present, the two best characterized neurotoxic HIV-1 proteins. We showed that gp120 and Tat are both present in the brain of HIV-1 infected patients and are toxic to neurons in-vivo and in-vitro. Exogenously-applied Tat depolarized neuronal membranes and caused biphasic increases of cytosolic calcium; the first increase was from intracellular stores by IP₃-dependant mechanisms and the second by glutamate-receptor mediated calcium influx. Tat significantly potentiated glutamate and NMDA receptor-mediated increases in cytosolic calcium by mechanisms dependant on IP₃-receptors and potentiated glutamate-mediated neuronal cell death. Blockade Of IP₃-receptors protected neurons from the toxic effects of Tat. Applications of gp120 to mixed neuron/astrocyte cultures resulted in increases of cytosolic calcium first in astrocytes and second in neurons. Gp120-induced increases in cytosolic calcium were blocked by inhibition of Na+/H+ exchange, and in neurons, by antagonists of L-type voltage-sensitive calcium channels and glutamate receptors. Sub-toxic amounts of Tat and gp120, when combined, produced synergistic increases of cytosolic calcium and neuronal cell death. Antagonists of NMDA receptors but not L-type calcium channels or Na+/H+ exchange reversed the combined neurotoxic effects of gp 120 and Tat. Together, these findings suggest that even very low levels of the HIV-1 proteins Tat and gp120 can combine to cause dysfunction and death of neurons in brain of HIV-1 infected individuals. Furthermore, our findings have identified mechanisms for and potential therapeutic strategies against HIV-1 dementia.