Human immunodeficiency virus-1 (HIV-1) and tuberculosis (TB) are significant global health issues today and the immunological correlates of protection to both diseases remain poorly defined. HIV-1 is the greatest risk factor for the development of TB and HIV-associated TB contributes significantly to the global TB burden, particularly in sub-Saharan Africa. The host T cell response to Mycobacterium tuberculosis (Mtb) is critical for control and is weakened in HIV-1 disease. However, the extent and precise mechanisms remain incompletely elucidated. Antiretroviral therapy (ART) for HIV-1 reduces TB risk in treated individuals significantly, although not to levels seen in HIV-uninfected individuals. This thesis studies HIV- and Mtb-specific T cell responses in 2 cohorts of individuals from a community with high HIV-1 and TB prevalence in Bloemfontein, South Africa. An analysis of HIV-specific CD8 T cell responses in Chapter 4, confirms the superior role of HIV-1 Gag-specific CD8 responses in controlling HIV-1 viraemia and demonstrates that the loss of such responses contributes to HIV-1 disease progression and likely susceptibility to opportunistic infection. I investigated the impact of HIV-1 infection on the Mtb-specific T cell response through a cross-sectional comparison of T cell responses in HIV-infected and HIV-uninfected individuals (Chapters 5 and 6). HIV-infected individuals had a significant depletion of both Th1 and Th17 CD4 responses to Mtb-specific antigens as well inhibition of Mtb-specific CD8 T cell responses, in comparison to those uninfected with HIV-1. PPD- and Rv2031c-specific responses were particularly reduced in HIV-infected individuals. Over a 12 month period of therapy, ART partially restored the Mtb-specific CD4 T cell response (Chapters 5 and 7). This effect was greater for Th1 than Th17 responses and had no detectable effect on the Mtb-specific CD8 response. However, despite some evident restoration, there remains a significant quantitative deficit in individuals on ART that is likely to contribute to persistent elevated TB risk. Overall, these data contribute to a better understanding of the mechanisms of susceptibility to TB during HIV-1 disease and ART, as well as of the correlates of protective immune responses to both pathogens.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:658433 |
| Date | January 2014 |
| Creators | Murray, Lyle W. |
| Contributors | Frater, Alexander John; Phillips, Rodney |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:c4a292ca-d49d-4aac-9de8-910836a96983 |
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