The Role of Affinity and Mechanism of Virus Attachment to Cells in Antibody-Dependent Enhancement and Neutralization of Flaviviruses
Obara, Christopher John
Flaviviruses are RNA viruses that cause significant morbidity and mortality worldwide. There are currently no specific therapeutics or clinically licensed vaccines available for a number of flaviviruses, including dengue virus (DENV) and West Nile virus (WNV). Protection against flaviviruses is most closely correlated with a robust neutralizing antibody response. Neutralization is governed by a stoichiometric threshold. Virus particles engaged by a number of antibody molecules that exceeds this threshold are neutralized, while those engaged by fewer remain infectious. If these infectious particles have enough antibody bound, they may paradoxically show enhanced binding and infectivity on cells expressing Fc-gamma receptors (FcRs), which bind to antibody. This phenomenon is known as antibody-dependent enhancement (ADE), and it has been implicated in more severe forms of disease during DENV infection.The number of antibodies required per virion for both neutralization and enhanced binding have been estimated using model cell lines, but the role of the target cell in modulating these numbers is unknown. In this dissertation, we examine the contribution of variables that affect the functional affinity of virus or virus-bound antibody for cellular attachment factors. Any parameters tested that were predicted to increase the efficiency of FcR-mediated virus binding to cells decreased the number of antibodies required to mediate ADE. The neutralizing potency of antibodies was increased only in situations where high affinity binding occurred between virus bound antibodies and FcRs. In contrast, changes in cellular expression of either FcRs or antibody-independent attachment factors had no effect on neutralization. This discrepancy can partially be explained by the clustered nature of virus attachment factors, suggesting that the function of antibodies may be dependent on the location of virus-cell contact.
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