Abstract
In a secondary dengue virus (DENV) infection, the presence of non-neutralizing antibodies (Abs), developed during a previous infection with a different DENV serotype, is thought to worsen clinical outcomes by enhancing viral production. This phenomenon is called antibody-dependent enhancement (ADE) of infection, and it has delayed the development of therapeutic Abs and vaccines against DENV, as they must be evaluated for the potential to induce ADE. Unfortunately, limited replication of DENV clinical isolates in vitro and in experimental animals hinders this evaluation process. We have, therefore, constructed a recombinant chimeric flavivirus (DV2ChimV), which carries premembrane (prM) and envelope (E) genes of type 2 DENV (DENV-2) R05-624 clinical (Thai) isolate in a backbone of Japanese encephalitis virus (Nakayama strain). DENV E-protein is the most important viral target, not only for neutralizing Abs, but also for infection-enhancing Abs. In contrast to DENV-2 R05-624, DV2ChimV replicated efficiently in cultured mammalian cells and was lethal in interferon-α/β–γ-receptor double-knockout mice. With DV2ChimV, we were able to perform neutralization assays, in vitro and in vivo ADE assays, and in vivo protection assays. These results suggest that the chimeric virus is a powerful tool for evaluation of Abs against DENV.
Highlights
In a secondary dengue virus (DENV) infection, the presence of non-neutralizing antibodies (Abs), developed during a previous infection with a different DENV serotype, is thought to worsen clinical outcomes by enhancing viral production
DENV-2 R05-624 started replicating slowly, reaching a peak titer of 1.2 × 104 focus-forming units (FFU)/mL at Day 3 p.i.; virus production completely ceased at Day 5 p.i. (Fig. 1d)
DENV-2 production was probably suppressed by the innate immunity in B7 cells because IFN-α and -β in infected B7 cells started to increase on Day 2 p.i and reached a maximum level at Day 5 p.i. (Supplementary Fig. S1)
Summary
In a secondary dengue virus (DENV) infection, the presence of non-neutralizing antibodies (Abs), developed during a previous infection with a different DENV serotype, is thought to worsen clinical outcomes by enhancing viral production. Anti-DENV antibodies (Abs) produced during primary infections are thought to contribute to secondary heterotypic infection by promoting efficient uptake of Ab–DENV immune complexes by cells bearing the Fc receptor, such as monocytes and m acrophages[5] This process, which is known as Abdependent enhancement (ADE), may explain why severe disease is more frequently observed in secondary/ subsequent heterotypic DENV infections. No study has developed alternative mouse models that focus on E and E-specific Abs. Here, we describe the construction of a recombinant chimeric flavivirus (DV2ChimV), which carried premembrane (prM) and envelope (E) genes of low passage-number DENV-2 R05-624 clinical isolate in a Japanese encephalitis virus (JEV) backbone. Our results demonstrated the potential of DV2ChimV for evaluation of anti-DENV Abs in vitro and in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
