Identification of multiple novel HIV-specific T-cell epitopes using HLA-associated HIV polymorphisms
Almeida, C., Bronke, C., Roberts, S., Cooper, D., Corkery, M., McKinnon, E., Ahmad, I., Keane, N., Chopra, A., Mallal, S., John, M. and Heckerman, D. (2009) Identification of multiple novel HIV-specific T-cell epitopes using HLA-associated HIV polymorphisms. In: 39th Annual Scientific Meeting of the Australasian Society for Immunology 2009, 6 - 10 December 2009, Gold Coast, QLD.
HIV adapts to T-cell immunity by mutating within or near HLA-restricted CD8-T cell epitopes and therefore HLA allele-specific HIV polymorphisms in a human population mark the immunogenic targets of CD8 T-cell responses relevant to that population in-vivo.
We used the imprints of HLA-associated T-cell selection generated from the analysis of a combined cohort of 800 anti-retroviral naïve, HLA-diverse, predominantly subtype B-infected individuals derived from national populations from the USA and Western Australia. The cohort consensus sequence spanning 13 amino acid windows around HLA associations was scanned with the ‘Epi-pred’ epitope prediction programme and was used to identify putative in-vivo selection CD8 T-cell targets (non-adapted epitopes) as well as HLA-adapted variants capable of inducing a de novo immune response (adapted epitopes). PBMC IFN-responses to predicted optimal length epitopes were quantified in ELISpot assays, taking into account the autologous HLA genotype and the autologous viral sequence of 200 individuals from a North American cohort.
In the analysis of the first 29 individuals, we identified nine possible novel epitopes with the predicting HLA restriction matching the genotype of the reacting PBMC. In many instances, the HLA-driven change led to loss of reactivity as predicted for classical CD8 T-cell escape, however more complex patterns of reactivity were seen, particularly for epitopes in the Nef region. The creation of an escape variant was shown to elicit IFN- responses, including equivalent or higher responses compared with the non-adapted epitopes, suggesting that HIV adaptation may create ineffective immune recognition in some cases. These results provide further insights into CD8 T cell responses against the virus and have implications for HIV vaccine design.
|Publication Type:||Conference Item|
|Murdoch Affiliation:||Institute for Immunology and Infectious Diseases|
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