Mechanism of differential Zika and dengue virus neutralization by a public antibody lineage targeting the DIII lateral ridge.

Haiyan Zhao,John M Errico,James E Crowe,Theodore C Pierson,Christopher A Nelson,Daved H Fremont,Michael S Diamond,Zengqin Deng,Lily Xu,Robin Bombardi,Kimberly A Dowd,Rachel Nargi

doi:10.1084/jem.20191792

Abstract

We previously generated a panel of human monoclonal antibodies (mAbs) against Zika virus (ZIKV) and identified one, ZIKV-116, that shares germline usage with mAbs identified in multiple donors. Here we show that ZIKV-116 interferes with ZIKV infection at a post-cellular attachment step by blocking viral fusion with host membranes. ZIKV-116 recognizes the lateral ridge of envelope protein domain III, with one critical residue varying between the Asian and African strains responsible for differential binding affinity and neutralization potency (E393D). ZIKV-116 also binds to and cross-neutralizes some dengue virus serotype 1 (DENV1) strains, with genotype-dependent inhibition explained by variation in a domain II residue (R204K) that potentially modulates exposure of the distally located, partially cryptic epitope. The V-J reverted germline configuration of ZIKV-116 preferentially binds to and neutralizes an Asian ZIKV strain, suggesting that this epitope may optimally induce related B cell clonotypes. Overall, these studies provide a structural and molecular mechanism for a cross-reactive mAb that uniquely neutralizes ZIKV and DENV1.

Highlights

Zika virus (ZIKV) typically causes a self-limiting febrile illness, with most infected individuals exhibiting minimal or no symptoms (Duffy et al, 2009)
Using structural and functional approaches, we characterized a DIII-lateral ridge (LR) monoclonal antibodies (mAbs) that is commonly elicited in humans against ZIKV and found to cross-react with dengue virus serotype 1 (DENV1), and determined the molecular basis of its inhibitory activities
We and others have previously described DIII-LR mAbs against WNV (Thompson et al, 2009), JEV (Fernandez et al, 2018), and ZIKV (Wang et al, 2019) that are capable of blocking viral membrane fusion, and similar mechanisms of action have been reported for flavivirus mAbs against other epitopes (Gollins and Porterfield, 1986; Füzik et al, 2018; Zhang et al, 2016; Vogt et al, 2009; Zhang et al, 2015; Cockburn et al, 2012)

Summary

Introduction

Zika virus (ZIKV) typically causes a self-limiting febrile illness, with most infected individuals exhibiting minimal or no symptoms (Duffy et al, 2009). Dengue virus (DENV) is genetically related to ZIKV, infects nearly 400 million people annually, and causes variable clinical disease ranging from a mild to severe febrile illness and lifethreatening dengue shock syndrome (Bhatt et al, 2013). Since its introduction and spread in the Western hemisphere in 2015–2016, ZIKV has emerged as a significant global health concern. Both ZIKV and DENV are principally transmitted by mosquitoes (Cao-Lormeau et al, 2016) and belong to the Flavivirus genus of the Flaviviridae family of single-stranded positivesense RNA viruses, which include West Nile (WNV), Japanese encephalitis (JEV), yellow fever, and the tick-borne encephalitis viruses (Lazear and Diamond, 2016). Antibodies against flaviviruses map to epitopes in all three domains, and those against DIII are among the most potent at neutralizing infection (Nybakken et al, 2005; Robbiani et al, 2017; Zhao et al, 2016; Shrestha et al, 2010; Sukupolvi-Petty et al, 2010)

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Conclusion