Certain HLA-B-restricted CD8+ T cell responses are associated with control of viremia
whereas HLA-Cw* restricted responses, including Gag epitopes are associated with high
viremia. To better understand the role of HLA-Cw* restricted epitopes in viral control,
HLA-Cw* restricted epitopes were optimally defined. Seventy eight study subjects from
a cohort of 451 chronically infected participants had HLA-Cw* restricted CD8+ T cells
responses as quantified by intracellular cytokine staining assessing IFN-γ secretion. Fine
mapping and HLA restriction of the optimally defined HLA-Cw* restricted epitopes were
performed using ELISPOT assay. Functional avidity of responses was assessed by
peptide dilution in an ELISPOT assay. Two novel HLA-Cw* restricted epitopes Cw*04-
TF10 (in reverse transcriptase) and Cw*08-RM9 (in gp120) were optimally defined. A
previously described epitope, Cw*07- KY11 (Nef) was the most frequently targeted
epitope in this cohort (30/78) and has high functional avidity compared to other HLA-Cw
restricted CD8+ T cell responses.
The polyfunctionality of HLA-B*57/5801-restricted Gag-specific HIV-1 CD8+ T cell
responses and HLA-Cw*07-KY11 restricted CD8+ T cell responses within the same
study subject was determined. Polyfunctionality of CD8+ T cell responses to HLAB*
57/5801 and HLA-Cw*07 restricted epitopes were determined in nine study subjects
assessing IFN-γ, TNF-α, IL-2, MIP-1β, and CD107a by multicolour flow cytometry.
Additionally gag and nef genes were sequenced from plasma. HLA-B*57/5801-restricted
IFN-γ-producing CD8+ T cell responses were of lower magnitude than HLA-Cw*07
responses (p=0.0012) for the nine subjects. The majority of responses were
monofunctional (75%), irrespective of HLA restriction. HLA-B*57/5801 and HLACw*
07 restricted CD8+ T cells did not differ significantly in polyfunctionality (p=0.84).
Possession of ≥3 functions correlated positively with CD4+ T cell counts (r=0.85;
p=0.006). The percentages of monofunctional CD8+ T cells inversely correlated with
CD4+ T cell counts (r=-0.79; p=0.05). There was no correlation between
polyfunctionality and viral load and sequence variation within targeted epitopes did not
impact polyfunctionality. These results suggest that polyfunctionality of HIV-1-specific
CD8+ T cells is associated with disease progression independent of restricting HLA
alleles, and that loss of these polyfunctional cells correlates with increased in the
frequency of monofunctional virus-specific CD8+ T cells. In addition, sequence variation
does not appear to significantly impact CD8+ T cell polyfunctionality in chronic HIV
infection. / Thesis (M.Med.)-University of KwaZulu-Natal, Durban, 2010.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ukzn/oai:http://researchspace.ukzn.ac.za:10413/9638 |
| Date | January 2010 |
| Creators | Mkhwanazi, Nompumelelo Prudence. |
| Contributors | Ndung'u, Thumbi. |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
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