Immunosenescence is the progressive loss of immune tissue that result from (i) functional, (ii) clonal or (iii) systemic changes to the cells or tissue that make up the immune system. While this process occurs gradually during the ageing process, there is overwhelming evidence to implicate HIV infection in driving all three aspects of immunosenescence by inducing high levels of immune activation. In the current literature, there is a dearth of data on the impact of HIV-2 infection or untreated perinatal HIV-1 infection in driving immunosenescence, and the key goal of this thesis is to mend this gap in knowledge. Both HIV-2 and paediatric HIV-1 infection provide excellent settings for verifying the mechanistic theories that relate to HIV-1-associated immunosenescence. The majority of HIV-2 infected individuals control their infection, which raises the question of how HIV-2 controllers are able to generate robust T-cell responses, when equivalent responses are rare in HIV-1 infected cohorts. Our hypothesis is that the former is an outcome of sustained or more robust homeostasis due to lower immune activation levels. Altogether, we show that primary immune resources are better preserved in HIV-2 than in HIV-1 infection - including more substantial HPC and naìˆve T-cell populations that correlate well with thymic output. The preservation of primary immune responses during HIV-2 infection is expected to contribute to robust effector functions and a younger phenotype of virus-specific memory T-cells. Accordingly, we show that HIV-2 specific memory T-cells reflect an earlier differentiated phenotype than HIV-1 specific T-cells, are highly polyfunctional and exhibit strong virus suppressive capabilities. In perinatally HIV-1 infected children - who by virtue of their age represent slow progressors - the presence of a hyperactive thymus may be sufficient to compensate against the early onset of immunosenescence and result in younger immune cell phenotypes. Yet, in measuring leucocyte telomere length and mtDNA content by qPCR, which qualify as biomarkers of senescence, we observed that leucocytes from vertically-infected Zimbabwean children present with shortened telomeres and an increase in mtDNA content, which signals the onset of advanced cellular senescence.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:729924 |
| Date | January 2016 |
| Creators | Glenn, Wong Choon Lim |
| Contributors | Rowland-Jones, Sarah |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://ora.ox.ac.uk/objects/uuid:40b13bda-dd4c-4a01-b144-43d80201dc52 |
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