Repository logo
 

The role of HLA-C restricted CD8+T cell responses in the control of HIV replication.

dc.contributor.advisorNdung'u, Peter Thumbi.
dc.contributor.authorMkhwanazi, Nompumelelo Prudence.
dc.date.accessioned2013-10-01T06:04:08Z
dc.date.available2013-10-01T06:04:08Z
dc.date.created2010
dc.date.issued2010
dc.descriptionThesis (M.Med.)-University of KwaZulu-Natal, Durban, 2010.en
dc.description.abstractCertain 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.en
dc.identifier.urihttp://hdl.handle.net/10413/9638
dc.language.isoen_ZAen
dc.subjectHIV infections.en
dc.subjectHIV infections--Immunological aspects.en
dc.subjectT cells.en
dc.subjectTheses--Paediatrics and child health.en
dc.titleThe role of HLA-C restricted CD8+T cell responses in the control of HIV replication.en
dc.typeThesisen

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Mkhwanazi_Nompumelelo_Prudence_2010.pdf
Size:
1.43 MB
Format:
Adobe Portable Document Format
Description:
Thesis

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.64 KB
Format:
Item-specific license agreed upon to submission
Description: