A major goal of our research is to understand the pathogenic mechanisms involved in retrovirus-induced cell death in the nervous and immune systems using a mutant of MoMuLV-TB virus called ts 1. ts 1 infected mice typically exhibit selective depletion of T cells and neurons, and the disease that results resembles human AIDS. Like HIV, ts 1 appears to destroy T cells directly but neurons indirectly. The latter is likely due to loss of glial redox support and by release of oxidants, neurotoxins (e.g. glutamate) and proinflammatory cytokines from infected glial cells. Until recently, we have understood very little about what leads to the loss of neurons and T cells after HIV or ts 1 infection. What we do know is that a single mutation in the ts 1 env gene results in accumulation of tsl gPr80ENV in the endoplasmic reticulum (ER) in infected cells, and that this abnormality is responsible for immunodeficiency and neurodegeneration in infected animals. ts 1 infects a number of cell types, but only in infected T cells and astrocytes is the transport of gPr80ENV-inefficient, resulting in accumulation of gPr80ENV in the ER. For this reason, work in our laboratory has been focused on the effects of ts 1 infection on these two cell types. We now know that this cell type-specific abnormal viral protein accumulation (at least in astrocytes) plays a critical role in the selective induction of apoptosis in these cells. In view of the several similarities between ts 1-induced and HIV-induced disease, it is interesting to note that recent studies by others now suggest a similar relationship between the retention of gp 160 in the ER and the cytopathic effects of HIV infection in CD4+ T cells. Our central hypotheses are that the ER is the primary site where ts 1 gPr80ENV-mediated apoptotic effects are initiated, and that the failure of tsl gPr80ENV to move out of the ER activates the ER overload response (EOR) and the unfolded protein response (UPR), with a subsequent calcium overload-induced mitochondrial stress, and with overproduction of reactive oxygen species and loss of glutathione in infected astrocytes, leading to death of astrocytes and T cells. With loss of thiol redox support from astrocytes and release of oxidants and neurotoxins from infected astrocytes, neuronal death is the end result. We propose now to determine whether the above hypotheses are correct, to determine how astrocytes kill neurons and to ascertain whether T cell death induced by ts 1 also involves gPr80ENV accumulation and oxidant stress. More important, we hope that the knowledge we gain from these studies will allow us to identify ways to prevent these events.
Our Specific Aims are: 1) To confirm that gPr80ENV accumulation, with resultant ER stress and mitochondrial stress induces oxidative apoptosis of ts 1-infected astrocytes, and to identify ways to prevent these events; 2) To determine the mechanisms by which uninfected neurons are indirectly killed by adjacent tsl-infected astrocytes in culture and in the brains of infected animals, and to identify ways to prevent these events, and 3) to determine whether gPr80ENV accumulation causes ER/mitochondrial stress leading to oxidant stress in T cells of infected animals, as it is in infected astrocytes, and to identify ways to prevent these events. ? ?
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