Molecular determinants of dengue virus 2 envelope protein important for virus entry in FcγRIIA-Mediated antibody-dependent enhancement of infection

Antibody-dependent enhancement (ADE) of infection may cause severe illness in patients suffering a secondary infection by a heterologous dengue virus (DENV) serotype. During ADE of infection, cross-reactive non- or poorly-neutralizing antibodies form infectious virus-Ab complexes with the newly infecting serotype and enhance virus infection by binding to the Fc gamma receptors (Fc gamma R) on Fc gamma R-bearing cells. In this study, we determined that molecular determinants of DENV2 envelope protein critical for virus entry during non-ADE infection are also required for ADE infection mediated by Fc gamma RIIA, and binding of virus-Ab complexes with Fc gamma RIIA alone is not sufficient for ADE of infection. The Fc gamma RIIA mainly plays an auxiliary role in concentrating the virus-Ab complex to the cell surface, and other primary cellular receptors are required for virus entry. Understanding the viral entry pathway in ADE of DENV infection will greatly facilitate rational designs of anti-viral therapeutics against severe dengue disease associated with ADE. Published by Elsevier Inc.