Antibody-dependent enhancement of heterotypic dengue infections involved in suppression of IFNgamma production

Antibody-dependent enhancement has been implicated in some outbreaks of epidemic dengue hemorrhagic fever, however, the mechanism of antibody-dependent enhancement is not well known. This study was conducted to investigate the cross-protection and cross-enhancement of dengue-2 virus infections by dengue-1 immune sera. It was found that dengue-1 immune sera at 1:5 dilution (n = 12) could neutralize dengue-2 infections in BHK-21 cells, as assessed by a standard plaque-reduction neutralization assay. Two-thirds of the dengue-1 immune sera at 1:25 dilution demonstrated neutralizing effects for dengue-2 infections, whereas, non-immune sera revealed no neutralization for dengue-2 infections in BHK-21 cells. Human mononuclear leukocytes in response to dengue-2 infections elicited a T cell helper 1 (Th1) response revealing induction of IFNgamma but not IL-4 production. Dengue-1 immune sera did not neutralize dengue-2 infections in mononuclear leukocytes. Subneutralizing titers of dengue-1 immune sera at 1:250, but not at 1:10 dilution, enhanced dengue-2 infections in mononuclear leukocytes (1.2 +/- 0.7 x 10(4) vs. 2.8 +/- 0.3 x 10(2) PFU/ml). The enhancement of dengue-2 infections in mononuclear leukocytes by dengue-1 immune sera at 1:250 was associated with an increase in the lymphocyte proliferation index, and a decrease in IFNgamma production (56 +/- 24 vs. 12 +/- 3 pg/ml). The addition of IFNgamma (0.1 microg/ml) suppressed significantly the antibody-dependent enhancement induced by dengue-1 immune sera, whereas the presence of anti-IFNgamma F(ab)2 antibody augmented the antibody-dependent enhancement effect. Results from this study suggest that suppression of Th1 response may be involved in the antibody-dependent enhancement of heterotypic dengue infections. Better regulation of Th1/Th2 reactions may be useful for prevention of heterotypic immune enhancement of dengue infections.