Antibodies against the Envelope Glycoprotein Promote Infectivity of Immature Dengue Virus Serotype 2.

PLoS One. 2012; 7(3): e29957
da Silva Voorham JM, Rodenhuis-Zybert IA, Ayala Nuez NV, Colpitts TM, van der Ende-Metselaar H, Fikrig E, Diamond MS, Wilschut J, Smit JM

Cross-reactive dengue virus (DENV) antibodies directed against the envelope (E) as well as predecessor membrane (prM) proteins are believed to contribute to the development of severe dengue disease by facilitating antibody-dependent enhancement of infection. We as well as others recently demonstrated which anti-prM antibodies render essentially non-infectious juvenile DENV infectious in Fc-receptor-expressing cells. Immature DENV particles are abundantly present in standard (st) virus preparations due to inefficient processing of prM to M during virus maturation. Structural analysis has revealed which the E protein is exposed in juvenile particles as well as this prompted us to investigate whether antibodies to E render juvenile particles infectious. To this end, we analyzed the enhancing properties of 27 anti-E antibodies directed against distinct structural domains. Of these, twenty-three bound to juvenile particles, as well as 15 enhanced infectivity of juvenile DENV in the furin-dependent manner. The significance of these commentary was subsequently tested in vivo using the well-established West Nile virus (WNV) mouse model. Remarkably, mice injected with juvenile WNV opsonized with anti-E mAbs or immune serum produced the lethal infection in the dose-dependent manner, since in the deficiency of antibody juvenile WNV virions caused no morbidity or mortality. Furthermore, enhancement infection studies with standard (st) DENV preparations opsonized with anti-E mAbs in the presence or deficiency of furin inhibitor revealed which prM-containing particles present within st virus preparations contribute to antibody-dependent enhancement of infection. Taken together, our results support the notion which antibodies against the structural proteins prM as well as E both can foster pathogenesis by enhancing infectivity of prM-containing juvenile as well as partially mature flavivirus particles.

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