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Title: Application of engineered T cell receptors to investigate the failure of cytotoxic T lymphocytes to eliminate the HIV reservoir
Author: Wallace, Zoë R.
ISNI:       0000 0004 7229 9611
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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HIV establishes a reservoir comprising long lived, latently infected CD4+ T cells and monocytic cells early during primary infection. This population represents a major barrier to an HIV cure. This thesis aimed to investigate the role of the immunological synapse in the failure of cytotoxic T lymphocytes (CTLs) to eliminate the HIV reservoir and the potential for engineered bispecific Immune-mobilising monoclonal T cell receptors Against Viruses (ImmTAV) to overcome this by redirecting fully functional CD8+ T cells against viral targets. A primary cell model of latency was used to investigate the expression of HIV Gag on latently infected cells and their susceptibility to ImmTAV-mediated elimination. A subset of cells expressed low levels of Gag without spreading infection and ImmTAV-redirected healthy donor CD8+ T cells were able to eliminate up to 40% of infected cells without latency reversal. CD8+ T cells from chronic HIV infected (CHI) donors showed impaired antiviral activity even with ImmTAV redirection. To investigate this further, confocal microscopy was used to study immunological synapse formation using primary CD8+ T cells from HIV-negative and CHI donors. CD8+ T cells from CHI donors were able to form conjugates with virus-infected cells but exhibited impaired synapse maturation, indicated by reduced Zap70 localisation, delayed microtubule-organising centre polarisation and impaired perforin recruitment to the synapse. ImmTAV redirection partially overcame these defects. Finally, the impact of antiretroviral agents on T cell mitochondrial function was explored. Exposure to zidovudine increased mitochondrial reactive oxygen species production and susceptibility to apoptosis. However, there was no evidence of impaired mitophagy. These data show that defects in CD4+/CD8+ T cell synapse maturation contribute to HIV persistence but nevertheless suggest that a subset of HIV reservoir cells may be susceptible to ImmTAV-mediated elimination. The therapeutic potential of ImmTAVs may depend in part on correction of CD8+ T cell exhaustion.
Supervisor: Dorrell, Lucy ; Chojnacki, Jakub Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Immunology ; T cells ; HIV ; Reservoir