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Title: Interactions of HIV-1 with antigen presenting cells
Author: Hewson, Timothy John
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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Data in this thesis demonstrate that gp120 causes a decline of cell-surface CD4 from human macrophages in vitro. A mechanism for this loss is proposed based on observation that it is significantly more substantial when CCR-5-binding gp120, derived from M-tropic HIV-1 is used as opposed to CXCR-4-binding gp120. CD4 loss is absent from macrophages that fail to express surface CCR-5 due to homozygosity for the naturally occurring ccr5D32 mutation. It appears that CD4 loss by this novel CCR-5-dependent mechanism requires cross-linking of CCR-5, CD4 and gp120 at the cell surface leading to receptor-mediated endocytosis of this protein complex. Confocal microscopy was used to visualise these endocytosed proteins inside macrophages and RT-PCR was used to investigate transcriptional regulation of CD4 and CCR-5 recovery. Endocytosis of the protein complex may change antigen presentation efficiencies. Possible implications for protective- and auto-immunity are discussed. This thesis also presents evidence that pre-treatment with gp120 leads to reduction in an APC's ability to stimulate antigen-specific proliferation of a T-cell line. Because this effect is not dependent on the tropism of the HIV-1 strain from which the gp120 is derived, an alternative mechanism to CD4-loss was sought. The hypothesis that APC dysfunction is due to HIV-1 subversion of physiological mechanisms involving prostaglandin and the Notch signalling pathway, leading to inappropriate tolerance induction, was examined. Treatment of macrophages and DCs with gp120 caused the transcriptional up-regulation of genes involved in the Notch pathway including Notch ligands, the presence of which on an APC has previously been shown to abrogate T-cell activation by the induction of an anergic phenotype. Preventing HIV-1 infection of APCs and the subsequent dysregulation of immune responses is a therapeutic goal. Branched, synthetic peptides based on discontinuous epitopes of gp120 and previously demonstrated to disrupt binding of CD4 and CCR-5 are shown to protect macrophages from infection with M-tropic HIV-1BAL. Possible refinements to peptide structure and their utility as anti-HIV-1 therapeutics or vaccines are discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available