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HLA-DRB1 alleles are associated with different magnitudes of dengue Virus–Specific CD4+T-Cell responses

Weiskopf, D., Angelo, M.A., Grifoni, A., O'Rourke, P.H., Sidney, J., Paul, S., De Silva, A.D., Phillips, E., Mallal, S., Premawansa, S., Premawansa, G., Wijewickrama, A., Peters, B. and Sette, A. (2016) HLA-DRB1 alleles are associated with different magnitudes of dengue Virus–Specific CD4+T-Cell responses. Journal of Infectious Diseases, 214 (7). pp. 1117-1124.

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Background. Each year dengue virus (DENV) infects 400 million human but causes symptomatic disease in only a subset of patients, suggesting that host genetic factors may play a role. HLA molecules that restrict T-cell responses are one of the most polymorphic host factors in humans.

Methods. Here we map HLA DRB1–restricted DENV-specific epitopes in individuals previously exposed to DENV, to identify the breadth and specificity of CD4+ T-cell responses. To investigate whether HLA-specific variations in the magnitude of response might predict associations between dengue outcomes and HLA-DRB1 alleles, we assembled samples from hospitalized patients with known severity of disease.

Results. The capsid protein followed by nonstructural protein 3 (NS3), NS2A, and NS5 were the most targeted proteins. We further noticed a wide variation in magnitude of T-cell responses as a function of the restricting DRB1 allele and found several HLA alleles that showed trends toward a lower risk of hospitalized disease were associated with a higher magnitude of T-cell responses.

Conclusions. Comprehensive identification of unique CD4+ T-cell epitopes across the 4 DENV serotypes allows the testing of T-cell responses by use of a simple, approachable technique and points to important implications for vaccine design.

Item Type: Journal Article
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
Publisher: Oxford University Press
Copyright: © 2016 The Author
Other Information: Presented in part: 5th Pan American Dengue Research Network Meeting, Panama City, Panama, 20–23 April 2016; Annual Meeting of the American Association of Immunologists, 13–17 May 2016, Seattle, Washington.
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