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CD8+ T-cell responses to different HIV proteins have discordant associations with viral load

Abstract

Selection of T-cell vaccine antigens for chronic persistent viral infections has been largely empirical. To define the relationship, at the population level, between the specificity of the cellular immune response and viral control for a relevant human pathogen, we performed a comprehensive analysis of the 160 dominant CD8+ T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa. Of the HIV proteins targeted, only Gag-specific responses were associated with lowering viremia. Env-specific and Accessory/Regulatory protein–specific responses were associated with higher viremia. Increasing breadth of Gag-specific responses was associated with decreasing viremia and increasing Env breadth with increasing viremia. Association of the specific CD8+ T-cell response with low viremia was independent of HLA type and unrelated to epitope sequence conservation. These population-based data, suggesting the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection, are of relevance to HIV vaccine design and evaluation.

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Figure 1: Location of the 160 dominant CD8+ T-cell epitopes targeted in the study population, and viral load associations of responses to these epitopes.
Figure 2: Breadth of protein-specific CD8+ T-cell responses in relation to viral load.
Figure 3: Comparison of viral loads in responders and HLA-matched nonresponders to epitopes in Gag and non-Gag proteins.
Figure 4: Comparison of viral loads in study subjects with responses to only Gag, to only Acc/Reg/Env protein epitopes, to both or to neither.
Figure 5: Comparison of the impact of HLA-A–, HLA-B– and HLA-C–restricted responses on viral load.
Figure 6: Protein-specific and epitope-specific CD8+ T-cell responses mediate selection pressure on HIV.

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Acknowledgements

This work is funded by the US National Institutes of Health (contract NO1-A1-15422, 2RO1AI46995-06 and R01AI067073), the Wellcome Trust (A.L. and P.G.), and the Mark and Lisa Schwartz Foundation. B.D.W. is a Doris Duke Distinguished Clinical Science Professor. P.G. is an Elizabeth Glaser Pediatric AIDS Foundation Scientist.

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Correspondence to Philip Goulder.

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Supplementary information

Supplementary Fig. 1

Viral loads (showing median values) of responders and non-responders expressing the relevant restricting HLA class I allele to the 160 identified CD8+ T cell responses. (PDF 928 kb)

Supplementary Fig. 2

Average entropy of the 18mer peptides within each protein (showing interquartile ranges and medians). (PDF 2467 kb)

Supplementary Fig. 3

Phenotypic frequencies of the HLA class I alleles present at >0.5% in the total study cohort (n=578), compared with phenotypic frequencies of the 272 subjects whose full-length viral sequences were determined. (PDF 1083 kb)

Supplementary Table 1

18mer peptides identified as the dominant epitopes targeted in this cohort, with the HLA class I restriction shown and, where defined, the optimal epitope within the 18mer peptide. (PDF 1085 kb)

Supplementary Table 2

Correlation in number of CD8+ T cell responses to each protein, and regression coefficients from linear regression of viral load on number of responses. (PDF 513 kb)

Supplementary Table 3

Number of epitopes containing polymorphisms associated with expression of the HLA class I molecule that was restricting the response. (PDF 1638 kb)

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Kiepiela, P., Ngumbela, K., Thobakgale, C. et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med 13, 46–53 (2007). https://doi.org/10.1038/nm1520

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