HLA-DRB1 Alleles Are Associated With Different Magnitudes of Dengue Virus-Specific CD4+ T-Cell Responses

Abstract

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.

Keywords: CD4+ T cells; Dengue virus; HLA; disease association.