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Title: The contribution of HLA class I-mediated CD8+ T cell responses to HIV-1 immune control and evolution
Author: Matthews, Philippa Clare
ISNI:       0000 0004 2692 114X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2009
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CD8+ T cells are a critical component of the adaptive immune response to HIV infection. The CD8+ response is orchestrated by presentation of HIV peptides in association with HLA Class I molecules on the surface of infected cells. Disease outcome varies according to HLA phenotype, with some alleles being characteristically associated with sustained viraemic control, and others with more rapid progression to AIDS. In order to evade the CD8+ T cell response, HIV selects escape mutations that reduce or abrogate HLA Class I presentation or disrupt recognition by T cell receptors. These mutations often occur in predictable combinations, termed HLA 'footprints', in response to selection pressure imposed by specific alleles. In the setting of a recent failed T cell vaccine trial, these studies aim to improve characterisation of favourable CD8+ T cell responses and to investigate the impact of HLA footprints on future viral evolution. The analyses highlight the potential benefit of selection of mutations that impose a viral fitness cost. By partially crippling the virus, these polymorphisms can contribute to viraemic control. The evolutionary effects of an HLA footprint are shown to be significant both in mediating convergent evolution, and in driving patterns of viral evolution across global populations. Studies of HLA-B*35 in HIV demonstrate that Class I alleles can have differential impacts according to the subtype of infecting virus. In this instance, there is evidence of disease control mediated by CD8+ T cell responses to HIV Gag. Finally, this work explores in vitro viral suppression assays as a tool for quantifying the CD8+ T cell response in individual subjects, presenting optimisation of techniques for assessing bulk and individual HLA-Class I restricted responses to HIV. Overall, these data contribute to the development of an HIV vaccine by enhancing our understanding of a successful CD8+ T cell response, suggesting the need to consider immunogens that match the strain of infecting virus, and investigating in vitro methods for assessing vaccine outcomes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available