Characterization of B-cell Responses to Zika Virus (ZIKV)

ABSTRACT

Objective: Most ZIKV infections occur in regions endemic for the related dengue virus (DENV). Anti-DENV antibodies have been demonstrated to cross-react with ZIKV. Some neutralize ZIKV infection while others mediate antibody-dependent enhancement (ADE), exacerbating ZIKV infection and complicating diagnosis of the etiologic agent. We aimed to characterize the humoral immune response in a ZIKV+, DENV- experienced individual in order to explore this anamnestic response and identify antibodies that may be useful in the development of therapeutic agents. Design and Methodology: Peripheral blood mononuclear cells (PBMCs) were collected from an individual (TT66) who was newly infected with ZIKV but had two previous DENV infections. Plasmablasts were isolated and analyses conducted using Atreca's Immune Repertoire CaptureTM technology. Monoclonal antibodies (mAbs) derived from TT66 during their acute and convalescent phase of ZIKV infection were screened in vitro for ZIKV and DENV binding and neutralization activity. Epitopes were then mapped using a shotgun mutagenesis approach. Results: We observed clonal expansion of two distinct antibody lineages representing 70% of total immunoglobulin sequences from TT66. We screened 18 mAbs representing two major lineages and five smaller families for neutralization and ADE between DENV and ZIKV. No highly typespecific mAbs were observed but rather a diverse pattern of neutralization, even within an individual lineage. Shotgun mutagenesis epitope mapping demonstrated epitopes for two of these broadly neutralizing mAb lineages lay within domain II ofE, close to the fusion loop. Conclusions: Results suggest that neutralizing antibody responses to ZIKV are extensively shaped by previous DENV exposure.