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.