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dc.contributor.authorStarling, Isabellaen
dc.date.accessioned2018-05-14T10:16:29Z
dc.date.available2018-05-14T10:16:29Z
dc.date.issued1998en
dc.identifier.urihttp://hdl.handle.net/1842/30011
dc.description.abstracten
dc.description.abstractLentiviruses such as Maedi-Visna Virus (MVV) in sheep and Human Immunodeficiency Virus (HIV) often cause a variety of neurological symptoms in later stages of infection. In sheep, MVV infection results in paralysis and ataxia, with post-mortem investigations revealing astrocytosis, demyelination and axonal damage. At present it is unclear how such neurodegeneration is mediated as MVV, like HIV, does not directly infect neurons. There is much debate as to the mechanisms involved in lentivirus related brain damage, centred around three main possibilities. Firstly, there may be a direct detrimental action of a viral fragment on neuronal cell types. Secondly, MVV infected cells may be releasing diffusible mediators such as cytokines which could cause neural damage or act on astrocytes and microglia causing them to produce factors to induce neurodegeneration. Thirdly, the prospect of an immune response occuring within the brain, involving infected macrophages or microglia, is highly probable.en
dc.description.abstractIn order to investigate the possible mechanisms at work in lentivirus induced neurodegeneration, several sets of experiments were carried out. Firstly, a putative model of MVV encephalopathy was established in severe combined immunodeficient (,scid) mice. Scid mice lack T and B cells and are thus unable to mount any immune response. Blood derived macrophages were obtained from healthy sheep and infected with MVV in vitro. These were intracerebrally injected into scid mice, as were uninfected macrophages, in order to assess the occurrence of any neural cell damage. Cell preparations of peripheral blood mononuclear cells (PBMCs), uninfected, supplemented with virus, or obtained from productively MVV infected sheep, were also administered to scid mice in the same manner, to evaluate the role of immune cells in causing any neurodegeneration. The results show that the administration of MVV infected macrophages produces greater gliosis and astrocytosis in the brains of these mice as compared to those injected with control uninfected macrophages or vehicle. However, the injections of PBMCs did not cause any detectable differences in astrocytes and microglia between the groups. No neuronal loss or demyelination was evident with any of the injections. These results suggest that neural cell disruption in MVV encephalopathy may be due to the presence of MVV infected macrophages in the Central Nervous System (CNS) of infected sheep, acting indirectly through the release of diffusible mediators.en
dc.description.abstractTo investigate further the underlying causes of these changes, the possible detrimental contribution of cytokines in this model was evaluated through the use of the reverse transcriptase-polymerase chain reaction (RT-PCR) of MVV infected and uninfected blood derived macrophages in vitro. The results show an increase in the levels of the pro-inflammatory cytokine interleukin-1 beta (TL-113) mRNA in MVV infected macrophages. Interpretation of this model therefore suggests that MVV exerts an indirect disruptive effect on neural cells via the release of pro-inflammatory cytokines from infected macrophages, causing microgliosis and astrocytosis which in turn lead to major disturbances of brain function.en
dc.description.abstractThe possibility of a neurotoxic action of a viral product was also investigated. Peptides derived from the basic region of the transactivating protein Tat from both MVV and HIV have previously been shown to be lethal to neurons in vivo and in vitro, through a mechanism believed to involve Nitric Oxide (NO)-mediated glutamate neurotoxicity and cytokines. The actions of the MVV tat peptide when injected intracerebrally in rats are diminished one week post-operatively by the Nmethyl-D-aspartate (NMDA) receptor antagonist (+)-5-methyl-10,ll-dihydro-5Hdibenzo[a,d]cyclohepten-5,10-imine maleate (MK801) and the Nitric Oxide Synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Here, its short term effects were examined and its neurotoxic mechanisms probed through the use of in vivo stereotaxic injections and pharmacologic manipulations. The results show that the MVV and HIV tat peptides were very rapidly neurotoxic, causing neuronal cell death within 0.5 hours, and displayed a distinctive and unusual lesion profile. Changes in astrocytes and microglia were also observed. The acute effects of the MVV tat peptide were blocked by MK801, an NMDA receptor antagonist. However, the administration of L-NAME, a NOS inhibitor, alpha melanocyte stimulating hormone (aMSH), a TNFa inhibitor, or 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo- (F)-quinoxaline (NBQX), a non-NMDA glutamate receptor antagonist, did not reduce the volume of the lesion. This suggests that the MVV tat peptide acts at the NMDA receptor to cause cell death either directly or via an excitotoxic mechanism.en
dc.publisherThe University of Edinburghen
dc.relation.isreferencedbyAlready catalogueden
dc.subjectAnnexe Thesis Digitisation Project 2018 Block 18en
dc.titleMechanisms and specificity of lentivirus neurotoxicityen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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