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Title: Mechanisms and specificity of lentivirus neurotoxicity
Author: Starling, Isabella
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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Maedi-Visna virus (MVV) infected macrophages cause disruption to brain glial cells, which may underly neurological dysfunctions. To investigate further the underlying causes of these changes, the reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out on MVV infected and uninfected blood derived macrophages in vitro. The results show an increase in levels of the pro-inflammatory cytokine interluekin-1 beta (IL-1β) mRNA in MVV infected macrophages. Interpretation of this data suggests that MVV infected macrophages may be exerting an indirect disruptive effect on neural cells via the release of IL-1β, causing microgliosis and astrocytosis. The neurotoxic actions of macrophage secreted products was also investigated. The supernatant of MVV infected macrophages was found to be acutely neurotoxic to rat cortical neurons in vitro, as was a peptide derived from the basic region of the MVV transactivating protein Tat. The administration of the tat peptide to rat striatum in vivo was also found to be neurotoxic. This effect was blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-5-meethyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK801) suggesting that the MVV rat peptide may either be having a direct neurotoxic effect on an action via glutamate mediated excitotoxicity. The findings of these experiments show that macrophages infected with MVV cause activation of astrocytes and microglia in the brains of scid mice. These changes may be caused by the release of the pro-inflammatory cytokine, IL-1β from infected macrophages, and may be detrimental to the normal function of the CNS. Furthermore, it is demonstrated here that MVV tat peptide is acutely neurotoxic in vitro and in vivo. The accumulation of this substance within the CNS as well as the persistent activation of glial cells may therefore lead to the neurodegeneration observed in lentiviral encephalopathies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available