Journal Article

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

Phillips, Elizabeth, Weiskopf, Daniela, Peters, Bjoern, Wijewickrama, Ananda, Sette, Alessandro, Mallal, Simon, Sidney, John, Paul, Sinu, O'Rourke, Patrick H, Premawansa, Gayani, Grifoni, Alba, De Silva, Aruna D, Angelo, Michael A, Premawansa, Sunil

2016

Overview

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 super(+) 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 super(+) 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.

• Subject: Flaviviridae