Control of retrovirus CNS disease by redox modulation

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The retrovirus tsl, a mutant of Moloney murine leukemia virus, like HIV infection in human, causes a progressive neuroimmunodegenerative (NID) syndrome in mice. Infection in the central nervous system by tsl results in neuronal loss with gliosis and spongiform lesions. Since glial cells but not neurons are infected with the virus, the neuropathogenic mechanism of tsl, like those of HIV, are most likely indirect. We previously demonstrated that accumulation of tsl precursor envelope proteins occurs in the endoplasmic reticulum (ER) of tsl infected astrocytes. This accumulation is accompanied by cell death in tsl-infected astrocytes. We also observed intracellular calcium accumulation and activation of NFkappaB in both astrocytes and neurons m the area of lesions in the CNS of tsl- infected mice. We therefore hypothesize that the excessive accumulation of tsl precursor envelope proteins in the astrocytic ER activates ER overload response resulting in excessive Ca2+ release that uncouples mitochondria causing release of toxic reactive oxygen species (ROS). In the CNS of tsl-infected mice there is a significant reduction of cysteine levels. A consequence of cysteine deficiency is the decrease in intracellular glutathione, which provides the major antioxidant defense in cells. This together with our recent finding that tsl decreases catalase levels in infected astrocytes and CNS suggests that the defense against oxidative stress in astrocytes and in the CNS is deficient. The oxidative damaged astrocytes may fail to support the developing neurons, and the release of ROS from astrocytes may also result in damage to neuronal membrane. Both of these effects could in turn result in neuronal death. Glutathione precursor N-acetyl cysteine, or peroxisome proliferator that activate production of catalase, have been shown to ameliorate both the tsl-induced astrocytic death in vitro and to prolong the latency period of tsl-induced neurodegeneration in vivo. Based on these preliminary observations we therefore propose here to: 1) Determine whether tsl induces thiol deficiency and oxidative damage in astrocytes in culture and in the CNS, 2) Elucidate the mechanisms underlying tsl-mediated thiol deficiency and redox stress in astrocytes and neurons in culture and in the CNS, and 3) Determine whether (a) NAC, (b) alpha-lipoic acid/dihydrolipoic acid, (c) peroxisome proliferators, such as PBA, that generate catalase, and (d) other antioxidants, e.g. Oxothiazolidine-4-carboxylate (OTC), either alone or in combination, can prevent or ameliorate tsl-induced astrocyte damage and neurodegeneration in the CNS. This project is focused on a well-characterized animal model. It addresses questions critical to our understanding of thiol deficiency and oxidative stress in retroviral-induced encephalopathy. It also provides a therapeutic rationale for controlling retroviral- induced neurodegeneration