NEUROTOXIC MECHANISMS OF TRANSACTIVATING PROTEIN TAT OF MAEDI-VISNA VIRUS

Infection by lentiviruses such as human immunodeficiency virus (HIV) a nd Maedi-Visna virus (MVV) is associated with neurodegenerative disord ers. We have investigated the neurotoxic mechanisms of a synthetic pep tide of transactivating protein rat of MVV in striatal neuronal cultur es, Tar peptide (but not control peptide) caused neuronal death, witho ut affecting glial viability, in a time- and dose-dependent manner. Si gnificant neuronal death was not observed until 6-8 h after tat peptid e application (2.35-2350 nM), whereas half maximal and maximal cell de ath was observed after 12 and 24 h respectively. Tat peptide neurotoxi city could be partially inhibited by blockade of either N-methyl-D-asp artate (NMDA)- or non-NMDA receptors, suggesting that excessive neuroe xcitation by glutamate or its analogues may contribute to tat-neurotox icity. Furthermore, when both these glutamate receptor subtypes were b locked simultaneously, an increased degree of neuroprotection was obse rved. Finally, tat peptide toxicity was also reduced by blockade of L- type calcium channels. Calcium imaging revealed that intracellular cal cium increases slowly upon tat application, predominantly due to entry of extracellular calcium. These results indicate that cellular calciu m entry through voltage-gated calcium channels following activation of both NMDA and non-NMDA receptors, and subsequent accumulation of intr acellular calcium may contribute to the neuronal death induced by tat protein.