Molecular Insights into Neutralization and Enhancement of Dengue Virus Infection in Monocytes

Abstract

Humoral response to dengue virus (DENV) protects only against the serotype that caused infection but not to the other three serotypes. Moreover, secondary infections may result in increased risk of dengue haemorrhagic fever or dengue shock syndrome. Hence, defining the determinants of successful antibody-mediated neutralization and enhancement of DENV would be important in the design of an effective dengue vaccine that protects against all four DENV serotypes. Here, we report that while serotype-specific antibodies can neutralize in the presence of Fc?R-mediated phagocytosis, DENV immune complexes formed with heterologous antibodies appear to neutralize only at levels where phagocytosis is inhibited. Moreover, increased antibody concentration was associated with increased size of the immune complexes formed, which appear to cross-link FcgRIIB to inhibit FcgR-mediated phagocytosis. In addition, we identified an ITIM-bearing receptor that antibody-opsonized dengue co-ligates to suppress interferon stimulated genes production and allowing DENV replication.