A recent study showed that a polymorphism ~35kb upstream of the HLA-C gene (-35 SNP) correlates with host control of HIV-1 in Caucasians, with the minor allele (C) associating with significantly lower set point viral loads than the major allele (T). A link between viral load and HLA-C is suggested by linkage of the two SNP alleles with different HLA-C alleles and by the fact that HLA-C, in contrast to HLA-A and -B, is not down-regulated by HIV-1 Nef protein. In addition, the -35C variant has been shown to associate with higher HLA-C messenger RNA expression in EBV-transformed B cell lines. We initially propose that increased surface expression of HLA-C in subjects with the protective SNP leads to increased breadth and magnitude of HLA-C restricted T cell responses, explaining the decrease in viral load in these subjects. This study initially investigates whether the -35 SNP correlates with the surface level of HLA-C using the monoclonal antibodies DT9, which recognises both HLA-C and HLA-E, and 3D12, which is specific for HLA-E. The lymphocytes from -35 CC subjects expressed a significantly higher level of surface HLA-C when compared to those from -35 TT subjects, but this difference in HLA-C expression can be attributed primarily to the very low expression of a single allelic product, HLA-Cw*07. Increased surface HLA-C should translate to functional differences between CC and TT subjects. This study confirmed that HLA-C restricted CD8 T cell responses against HIV-1 do exist, even for HLA-Cw*07, but represent a minority of total T cell responses. They were detected in all -35 SNP genotypes but there were no functional differences, making it unlikely that the protective effect of this SNP on viral load set point could be accounted for solely by HLA-C restricted T cell responses. Finally, a viral suppression assay was used to investigate the capacity of CD8 T cells to suppress HIV-1 replication in Caucasian and African subjects. We provide evidence that the -35 SNP effect on viral load is indeed T cell mediated. However, we suggest that the protective effect of the -35 SNP on viral load set point manifests as a result of linkage disequilibrium of this polymorphism with both favourable and unfavourable HLA-B and HLA-C alleles.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:558285 |
| Date | January 2011 |
| Creators | Corrah, Tumena Wandifa |
| Contributors | McMichael, Andrew |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:456f2b57-55de-42ed-83ac-bcbd1d869bd0 |
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