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Title: The role of dendritic cells in determining the breadth and epitope specificity of the initial CD8+ T cell response during acute HIV-1 infection
Author: Partridge, Thomas
ISNI:       0000 0004 6497 8614
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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During acute HIV-1 infection (AHI), CD8+ T cell responses are initially induced to only 1-3 viral epitopes in many patients, and Nef-derived epitopes are very commonly targeted. The earliest CD8+ T cell responses decrease in magnitude as viraemia begins to decline, and are followed by delayed expansion of subsequent waves of responses of broader epitope-specificity. In this thesis, the hypotheses that prevalent presentation of Nef-derived epitopes by dendritic cells (DCs) favours priming of Nef-biased CD8+ T cell responses in AHI, and that impairments in DC function after the first responses are primed delay expansion of responses of additional specificities, were explored. Mechanisms of impairment of DC function in AHI were not definitely identified, although preexposure of monocyte-derived DCs to IFN&alpa;, which is rapidly induced during AHI, was shown to reduce TLR3-induced co-stimulatory molecule expression and affect the quality of the CD8+ T cell response primed in vitro. Using mass spectrometry-based immunopeptidomics, novel HLA class Irestricted HIV-1 epitopes presented by HIV-1-infected CD4+ T cells were characterised, including epitopes derived from the 5' "untranslated" region of the HIV-1 genome. High ratios of Nef/Gag protein were found associated with extracellular vesicles (EVs) in the plasma of HIV-1+ patients during early, chronic and treated infection. Rather than CD4+ T cells, HIV-1-infected macrophages were identified as a potential source of these Nef-containing EVs. Utilising an in vitro DC crosspresentation assay incorporating immunopeptidomics, cross-presented epitopes were found to derive preferentially from proteins that were more abundant or membrane-associated. Multiple crosspresented HIV-1 (mainly Gag-, Pol- and Env-derived) epitopes were identified, but HIV-1-infected CD4+ T cells were not found to be a source of Nef for cross-presentation. Collectively, these results extend understanding of how DCs control CD8+ T cell immunodominance and expansion during AHI, and could potentially be exploited in future development of novel prophylactic and therapeutic strategies against HIV-1.
Supervisor: Borrow, Persephone ; Kessler, Benedikt Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available