Original antigenic sin in dengue revisited.

The four dengue virus serotypes (DENV-1 to -4) cause the most important arthropod-borne viral disease of humans, with ∼100 million cases each year and over 3 billion people at risk for infection (1). The immune response to DENV infection is complex, because it can be either protective or pathogenic. The “original antigenic sin” in secondary (2°) DENV infections is defined as the dominance of cross-reactive antibodies or T-cell responses to a first infecting DENV serotype (the “original antigen”) over the current infecting serotype. In acute DENV infections, cross-reactive T-cell responses have been associated with more severe disease, consigning cross-reactive T-cell responses to a pathogenic role (2, 3). In this issue of PNAS, Weiskopf et al. (4) challenge the idea that cross-reactive T-cell responses are only associated with pathogenesis by demonstrating that although CD8 T-cell responses were indeed skewed toward the first DENV infection, this did not result in impaired responses, either qualitatively or quantitatively. Furthermore, they found that higher magnitude T-cell responses were associated with HLA alleles that have been linked to reduced susceptibility to severe dengue. Thus, these results suggest that human cross-reactive T-cell responses can be associated with a robust and multifunctional response that can induce protection, as has been shown in dengue mouse models (5–7).