Loss of immune reactivity due to HIV mutational escape is well described. Data generated from a large population-based study (n>800) suggested that certain CD8 T cell epitopes are created as a result of HIV adaptation and are associated with enhanced viral replication. Here we sought to investigate the HLA-restricted T-cell responses associated with seven such adaptations

Almeida, C.M.

Bronke, C.

Chopra, A.

James, I.

John, M.

Keane, N.M.

Krishnan, T.

Laird, R.

Mallal, S.

Roberts, S.G.

Retrovirology

English

PubMed

James I

Mallal S

Bronke C

Almeida C

Krishnan T

Chopra A

Laird R

Roberts S

Keane N

John M

Directory of Open Access Journals

P09-15. Selection of higher avidity HLA-restricted T cell responses as a viral adaptation strategy

Background

Loss of immune reactivity due to HIV mutational escape is well described. Data generated from a large population- based study (n>800) suggested that certain CD8 T cell epitopes are created as a result of HIV adaptation and are associated with enhanced viral replication. Here we sought to investigate the HLA-restricted T-cell responses associated with seven such adaptations.



Methods 

180 cryopreserved PBMC samples from 112 patients were assayed for IFN- γ production and functional avidity to HIV peptides in ELISpot assays. CTL lines generated from short term PBMC cultures were confirmed and phenotyped by flow cytometry and cytotoxicity was assessed by chromium release. 



Results 

Responses were detected to non-adapted peptides in 48 samples (327 median [68–3067] range spot forming units (SFU)/10 6 cells) and adapted peptides in 54 samples (317 [63–2332] SFU/10 6 ). Responses to both non- and adapted peptides were detected in 19% (35/180) of samples (480[68–2225], 638[74–2332] SFU/10 6 respectively). Overall, responses to adapted epitopes were significantly greater than responses to non-adapted epitopes in patients with detectable viral load in screening assays (n = 14, p = 0.0413, Wilcoxon Rank Sum Test) and when half maximal peptide concentration data was analysed (p < 0.05 paired t-test). The frequency of IFN- γ producing cells from cultured CTL restricted by HLA-C*0702- KY11 (n = 7) was higher in central memory (p = 0.03) and effector memory CD8 T cell (p = 0.02) populations from adapted epitope (KRQEILDLWVY) stimulated cultures compared with non-adapted epitope (KRQDILDLWVYY) stimulated T cells. No difference in central or effector memory population size or IL-2 production was detected and preliminary data from chromium release assays suggests that CTL cultured with adapted peptides have differential killing against adapted versus non-adapted epitopes. 



Conclusion 

These data suggest that some high avidity and high IFN- γ - producing CD8 T cell responses are the result, rather than the cause, of viral adaptation. These data have implications for vaccine development

Keane, N.

Roberts, S.

Almeida, C.

Research Repository

N Keane

S Roberts

R Laird

A Chopra

T Krishnan

C Almeida

C Bronke

S Mallal

I James

M John

Crossref

BioMed  CentralPage 1 of 1(page number not for citation purposes)RetrovirologyOpen Access Poster presentationP09-15. Selection of higher avidity HLA-restricted T cell responses as a viral adaptation strategyN Keane*, S Roberts, R Laird, A Chopra, T Krishnan, C Almeida, C Bronke, S Mallal, I James and M JohnAddress: Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Perth, Australia* Corresponding author    BackgroundLoss of immune reactivity due to HIV mutational escapeis well described. Data generated from a large population-based study (n>800) suggested that certain CD8 T cellepitopes are created as a result of HIV adaptation and areassociated with enhanced viral replication. Here wesought to investigate the HLA-restricted T-cell responsesassociated with seven such adaptations.Methods180 cryopreserved PBMC samples from 112 patients wereassayed for IFN-γ production and functional avidity toHIV peptides in ELISpot assays. CTL lines generated fromshort term PBMC cultures were confirmed and pheno-typed by flow cytometry and cytotoxicity was assessed bychromium release.ResultsResponses were detected to non-adapted peptides in 48samples (327 median [68–3067] range spot forming units(SFU)/106 cells) and adapted peptides in 54 samples (317[63–2332] SFU/106). Responses to both non- andadapted peptides were detected in 19% (35/180) of sam-ples (480[68–2225], 638[74–2332] SFU/106  respec-tively). Overall, responses to adapted epitopes weresignificantly greater than responses to non-adaptedepitopes in patients with detectable viral load in screeningassays (n = 14, p = 0.0413, Wilcoxon Rank Sum Test) andwhen half maximal peptide concentration data was ana-lysed (p < 0.05 paired t-test). The frequency of IFN-γ pro-ducing cells from cultured CTL restricted by HLA-C*0702-KY11 (n = 7) was higher in central memory (p = 0.03) andeffector memory CD8 T cell (p = 0.02) populations fromadapted epitope (KRQEILDLWVY) stimulated culturescompared with non-adapted epitope (KRQDILDLWVY)stimulated T cells. No difference in central or effectormemory population size or IL-2 production was detectedand preliminary data from chromium release assays sug-gests that CTL cultured with adapted peptides have differ-ential killing against adapted versus non-adaptedepitopes.ConclusionThese data suggest that some high avidity and high IFN-γ-producing CD8 T cell responses are the result, rather thanthe cause, of viral adaptation. These data have implica-tions for vaccine development.from AIDS Vaccine 2009Paris, France. 19–22 October 2009Published: 22 October 2009Retrovirology 2009, 6(Suppl 3):P128 doi:10.1186/1742-4690-6-S3-P128<supplement> <title> <p>AIDS Vaccine 2009</p> </title> <editor>Anna Laura Ross</editor> <note>Meeting abstracts – A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1742-4690-6-S3-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1471-2105-10-S12-info.pdf</url> </supplement>This abstract is available from: http://www.retrovirology.com/content/6/S3/P128© 2009 Keane et al; licensee BioMed Central Ltd. 

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P09-15. Selection of higher avidity HLA-restricted T cell responses as a viral adaptation strategy

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