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

Abstract

Cross-reactive dengue virus (DENV) antibodies directed against the envelope (E) and precursor membrane (prM) proteins are believed to contribute to the development of severe dengue disease by facilitating antibody-dependent enhancement of infection. We and others recently demonstrated that anti-prM antibodies render essentially non-infectious immature DENV infectious in Fcγ-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 that the E protein is exposed in immature particles and this prompted us to investigate whether antibodies to E render immature particles infectious. To this end, we analyzed the enhancing properties of 27 anti-E antibodies directed against distinct structural domains. Of these, 23 bound to immature particles, and 15 enhanced infectivity of immature DENV in a furin-dependent manner. The significance of these findings was subsequently tested in vivo using the well-established West Nile virus (WNV) mouse model. Remarkably, mice injected with immature WNV opsonized with anti-E mAbs or immune serum produced a lethal infection in a dose-dependent manner, whereas in the absence of antibody immature 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 absence of furin inhibitor revealed that prM-containing particles present within st virus preparations contribute to antibody-dependent enhancement of infection. Taken together, our results support the notion that antibodies against the structural proteins prM and E both can promote pathogenesis by enhancing infectivity of prM-containing immature and partially mature flavivirus particles.

The interaction between claudin-1 and dengue viral prM/M protein for its entry

“…This is evidenced by inefficient infectivity and high percentage of immature progeny virus in both mammalian and insect cells. Recently, it has been reported that during entry step, the pr-capped fusion loop of E protein could be cleaved by furin, allowing conformational change and fusion of E protein, which renders immature virus infectious (da Silva Voorham et al, 2012;Rodenhuis-Zybert et al, 2011). In the present study, our data provide supporting evidence that immature particles can also interact with claudin-1 protein on the cell surface, and might be capable to entry into the target cells via this interaction.…”

DENV-2 subunit proteins fused to CR2 receptor-binding domain (P28)-induces specific and neutralizing antibodies to the Dengue virus in mice

“…High virus-neutralizing antibody titers (e.g., > 200) are generally associated with protection from viraemia, when measured using a plaque assay. 45,46 Despite our encouraging results, the increase in antibody levels (detected by ELISA) did not reflect the level of neutralizing activity. Interestingly, this observation may provide a clue to the availability of the epitopes that crosslink BCR with the CD21/ CD19/CD81 complex (the explanation of the adjuvanticity is in the constructions).…”

West Nile Virus: Biology, Transmission, and Human Infection

“…Immature or partially mature flavivirus particles of both DENV and WNV have been shown to account for up to as much as 40% of the total virus population in a given infection (135). While they were traditionally thought to be noninfectious, several recent studies have shown that immature WNV particles can be highly immunogenic and infectious in vitro and in vivo when bound by antibodies against the E or prM protein (43,51,179). These antibody-bound immature virus particles enter immune cells via the Fc receptor, resulting in productive infection.…”