HLA-Restricted T-cell responses to Immune-escape variants are detectable in chronic HIV-infection
Keane, N.M., Laird, R., Chopra, A., Maiden, T., Almeida, C., Mallal, S. and John, M. (2008) HLA-Restricted T-cell responses to Immune-escape variants are detectable in chronic HIV-infection. In: AIDS Vaccine 2008, 13 - 16 October, Cape Town, South Africa.
Background: HIV-1 mutational escape from a suppressive epitope- specific T-cell response has been well described. Analysis of HLA allele associated HIV polymorphism in a large populationbased study (n¼800) suggests that HIV adaptation may also lead to the creation of certain epitopes that induce responses favourable to the virus, rather than the host. We therefore sought to investigate the presence and functionality of the HLA-restricted T-cell responses against three such epitopes identified by the genetic analysis; pol (424–432) QIYPGIKVR (HLA-A*0301), pol (724– 734) QEEHEKYHSNW (HLA-B*4402) and Nef (105–115) KRQEILDLWVY (HLA-C*0702) in individuals drawn from the analysed population.
Methods: Cryopreserved PBMC from 68 patients in the WA HIV Cohort Study [HLA-A*0301 (n¼12), HLA-B*4402 (n¼30) and HLA-C*0702 (n¼26)] were assayed for the presence of IFN-g responses upon stimulation with predicted adapted and nonadapted (‘wild type’) peptides by ELISpot assay. Functional avidity was ascertained by peptide dilution and autologous epitope sequences were determined from contemporaneous plasma samples in patients with detectable HIV viral load (n¼9).
Results: IFN-g was detected in PBMC samples from all patients after stimulation with anti-CD3 or CEF. IFN-g responses to the predicted non-adapted and adapted HIV peptides were detected in 13 of 68 patients tested. Adapted peptides induced IFN-g responses in 8 HLA-C*0702 patients (median-500, range 150–1110 spots/ million cells), four HLA-B*4402 patients (median-310, range 160–480 spots/million cells) and one HLA-A*0301 patient. In 5 cases, the adapted peptide-specific response had greater functional avidity than the non-adapted peptide. Adapted autologous sequences were detected in 3 patients who concurrently demonstrated IFN-g responses.
Conclusion: Despite modest levels of epitope-specific IFN-g overall in this treatment-experienced patient group, HLA-restricted responses against adapted epitopes were demonstrable, even displaying higher avidity than the non-adapted forms in 5 cases, suggesting a functional basis for adaptation driving creation of epitopes. These data have implications for epitope inclusion criteria in HIV vaccine design.
|Publication Type:||Conference Item|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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