Differential Serotype Specificity in the IgG Subclass Profile of the Anti-Domain III Response Elicited by Dengue...

Dengue is a potentially fatal disease caused by any of the four serotypes of dengue virus complex (DENV1-4). Domain III (DIII) of the envelope protein mediates early virus:cell interactions and is target of potent neutralizing antibodies. Little data is available on the dynamic of IgG subclasses in anti-DIII response elicited during viral infection. Fifty-eight human sera were used to characterize the IgG subclass profile of the anti-DIII antibody response in terms of abundance and serotype-specificity. Immunodominant epitopes were also determined using 70 Ala-mutants of a recombinant DIII protein that spans residues with more than 15% of the exposed area in the virion. IgG1 and IgG3 were found as the subclasses that react to control primary infections while a significant response was detected for all IgG subclasses in response to secondary infections. Anti-DIII IgG1 exhibits a distinctive pattern of serotype-specificity with respect to the other IgG subclasses in the recognition of recombinant DIII proteins corresponding to the four DENV serotypes. The dominant epitope of IgG1 is located in the FG-loop, which is characterized by high variability in its amino acid sequence. In contrast, the dominant epitopes of IgG2, IgG3, and IgG4 were defined as regions enriched in complex- and subcomplex conserved residues such as the A-strand and the AB-loop of DIII. IgG1 plays a prominent role in neutralizing circulating DENV during infection. A balanced and timely response of the different IgG subclasses is critical in the evolution of dengue disease.