Effect of highly active antiretroviral therapy (HAART) on HIV-1 tat protein-induced neurotoxicity.
Background: HIV-1-trans-activating (Tat) protein has been associated with development of HIVassociated neurocognitive disorder (HAND). Previous studies have demonstrated that Tat protein causes neurotoxicity through an increase in reactive oxygen species (ROS) leading to damage of proteins and other cellular components. Tat has also been shown to cause excessive production of pro-inflammatory cytokines. However the role of antiretroviral agents in the neuropathology of HIV is not known. The objective of this study was to investigate whether a combination of antiretroviral drugs (Zidovudine, Lamivudine and Efavirenz, a highly active antiretroviral therapy, HAART) is effective in reducing the toxic effects of Tat protein in the rat hippocampus. Materials and methods: Male Sprague-Dawley rats were divided into four groups (n=10 per group). Each rat received bilateral intrahippocampal injection of either Tat protein (5μg/10μL) or vehicle, followed 7 days later by a combination of antiretroviral drugs (Zidovudine 12mg/kg, Lamivudine 6mg/kg and Efavirenz 24mg/kg) or saline injected intraperitoneally, twice a day, for 7 days. After treatment, animals were sacrificed and hippocampal tissue was collected for analysis of cleaved caspase-3, 4- hydroxynonenal (NHE), tumor necrosis factor alpha (TNF-α), phosphorylated extracellular signalregulated kinase (pERK) and Synaptophysin. Results: Tat increased cleaved caspase-3 levels in the hippocampus. Antiretroviral treatment decreased the Tat-induced increase in cleaved caspase-3. Tat increased HNE, a marker of lipid peroxidation and reduced hippocampal synaptophysin. The latter Tat-induced effects were not reversed by antiretroviral treatment. The antiretroviral drug combination activated the pERK pathway and increased TNF-α levels in hippocampal tissue, independent of Tat infusion. Discussion: Our findings showed that antiretroviral drugs reversed Tat-induced cleaved caspase-3, reducing apoptosis but did not reverse Tat-induced increase in lipid peroxidation and the synaptic marker, synaptophysin. The evidence suggests that the combination of antiretroviral drugs may be toxic, elevating hippocampal pERK and TNF-α levels. However, these effects could also be beneficial to the individual, since TNF-α has been shown to inhibit viral replication. The present results provide novel insight into the mechanism of antiretroviral action.