Abstract
Zika virus (ZIKV) specific neutralizing antibodies hold great promise for antibody-based interventions and vaccine design against ZIKV infection. However, their development in infected patients remains unclear. Here, we applied next-generation sequencing (NGS) to probe the dynamic development of a potent and protective ZIKV E DIII-specific antibody ZK2B10 isolated from a ZIKV convalescent individual. The unbiased repertoire analysis showed dramatic changes in the usage of antibody variable region germline genes. However, lineage tracing of ZK2B10 revealed limited somatic hypermutation and transient expansion during the 12 months following the onset of symptoms. The NGS-derived, germline-like ZK2B10 somatic variants neutralized ZIKV potently and protected mice from lethal challenge of ZIKV without detectable cross-reactivity with Dengue virus (DENV). Site-directed mutagenesis identified two residues within the λ chain, N31 and S91, that are essential to the functional maturation of ZK2B10. The repertoire and lineage features unveiled here will help elucidate the developmental process and protective potential of E DIII-directed antibodies against ZIKV infection.
Highlights
Zika virus (ZIKV), a member of the Flavivirus genus of the Flaviviridae family, is an emerging mosquito-borne pathogen
The VL germline gene of ZK2B10, IGLV147, displayed 5.72% somatic hypermutation (SHM) at Day 15, and 6.70 to 9.04% at other time points studied (Figure S2, right). These results suggest a drastic shift in repertoire composition likely caused by a rapid plasmablast response during the acute phase of ZIKV infection
D39 is within the HCDR1 loop, it forms hydrogen bonds with Y115 and Y117 on the opposite side of the HCDR3 loop, stabilizing the HCDR3 conformation (Figure 5C). These results provide further evidence that the ZK2B10 lineage was generated during the naïve B cell response to acute ZIKV infection, with critical residues encoded by the germline gene
Summary
Zika virus (ZIKV), a member of the Flavivirus genus of the Flaviviridae family, is an emerging mosquito-borne pathogen. ZIKV is closely related to other flaviviruses such as dengue (DENV 1, 2, 3, and 4), yellow fever (YFV), West Nile (WNV), Japanese encephalitis (JEV), and tick-borne encephalitis (TBEV) viruses [1]. Since ZIKV was first identified in 1947 among rhesus macaques in the Zika forest of Uganda, its new variants have become increasingly prevalent and have adapted to the human population as recent outbreaks spread across the Americas, Caribbean, and Southeast Asia [2,3,4,5]. The high prevalence of the vectors and the continuing evolution of viral species have raised serious concerns about public health and ZIKV-related disease control [11]
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