Antibody-dependent enhancement of heterotypic dengue infections involved in suppression of IFNγ 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 IFNγ 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 × 104 vs. 2.8 ± 0.3 × 102 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 IFNγ production (56 ± 24 vs. 12 ± 3 pg/ml). The addition of IFNγ (0.1 μg/ml) suppressed significantly the antibody‐dependent enhancement induced by dengue‐1 immune sera, whereas the presence of anti‐IFNγ 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. J. Med. Virol. 63:150–157, 2001. © 2001 Wiley‐Liss, Inc.