The tempo of HIV disease progression might rest with particular characteristics of certain HLA class I molecules, and the CD8+ T cell populations, which they dictate. Therefore we wanted to investigate if CD8+ T cell quality in HIV infection determines disease progression. To do this we used patients recruited from the UK arm of the SPARTAC clinical trial (n=155) that were acute (seroconverted within the previous 2 months, n=5) or early infected (seroconverted within the previous 6 months, n=150). These patients were followed into chronic infection (infected for 1 year, n= 117). To determine CD8+ T cell quality we developed novel HLA class I CD8null tetramers, which allow direct detection of high avidity CD8+ HIV -specific T cells ex vivo. Furthermore, by FACS analysis we analysed high and low avidity HIV -specific T cell T EMRA lineage differentiation (populations defined by CCR7, CD45RA and CD27) and T cell exhaustion (defined by PD-l, TIM-3 and LAG-3 expression). We show that high avidity HIV- specific T cells are present in both early and chronic HIV infection. A significantly greater proportion of CD8+ HIV -specific T cell populations restricted by HLA-B molecules are high avidity in comparison to HLA-A restricted populations (p<O.05). This is particularly prominent in HLA B*2705 KKlO specific populations (p-cfl. Ol ). The T EM RA differentiation of CD8+ HIV -specific T cells restricted by different HLA class I molecules differs, independent of T cell avidity. However, the T EMRA lineage differentiation of HIV -specific T cell populations fails to influence disease progression. HIV -specific T cell populations are significantly more exhausted than the total CD8+ T cell population (p<O.OOl), with high avidity HIV -specific T cell population being responsible for the majority of this exhaustion (p<O.Ol). Despite this the proportion of exhausted HIV -specific T cells does not correlate with HIV plasma viral loads. No clear relationship was found between CD8+ T cell quality, as measured by T cell avidity, T EMRA differentiation and T cell exhaustion and HIV disease progression.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:558438 |
| Date | January 2010 |
| Creators | Hickling, Stephen J. |
| Contributors | Phillips, Rodney |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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