Abstract
The intricate lattice of Gn and Gc glycoprotein spike complexes on the hantavirus envelope facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Through study of a neutralizing monoclonal antibody termed mAb P-4G2, which neutralizes the zoonotic pathogen Puumala virus (PUUV), we provide a molecular-level basis for antibody-mediated targeting of the hantaviral glycoprotein lattice. Crystallographic analysis demonstrates that P-4G2 binds to a multi-domain site on PUUV Gc and may preclude fusogenic rearrangements of the glycoprotein that are required for host-cell entry. Furthermore, cryo-electron microscopy of PUUV-like particles in the presence of P-4G2 reveals a lattice-independent configuration of the Gc, demonstrating that P-4G2 perturbs the (Gn-Gc)4 lattice. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses.
Highlights
Rodent-borne hantaviruses are enveloped, negativesense RNA viruses found worldwide in small mammals (Jonsson et al, 2010; Watson et al, 2014)
While mAb P-4G2 has been shown to be potently neutralizing against Puumala virus (PUUV), with a mAb concentration of ~4 nM (0.6 mg/ml) (Lundkvist and Niklasson, 1992) resulting in 80% inhibition of PUUV infection in focus reduction neutralization tests (Heiskanen et al, 1997; Lundkvist and Niklasson, 1992; Lundkvist et al, 1993c), there has been a paucity of information with regard to the structural basis for neutralization by this or any other Gcspecific antibody
We provide a molecular-level description of the epitope targeted by mAb P-4G2, a host-derived antibody that potently neutralizes PUUV, a zoonotic hantavirus prevalent in Northern Europe and Russia
Summary
Rodent-borne hantaviruses (genus Orthohantavirus, family Hantaviridae) are enveloped, negativesense RNA viruses found worldwide in small mammals (Jonsson et al, 2010; Watson et al, 2014). Recent studies have reported crystal structures of both Gn (Li et al, 2016; Rissanen et al, 2017) and Gc (Guardado-Calvo et al, 2016; Willensky et al, 2016) ectodomains, and their higher-order, tetrameric organization has been postulated based on biochemical characterization (Hepojoki et al, 2010) and cryo-electron microscopy reconstructions of purified virions (Battisti et al, 2011; Huiskonen et al, 2010; Li et al, 2016). We structurally characterize the epitope of mAb P-4G2, a potently neutralizing antibody derived following experimental infection of bank voles with Puumala virus (PUUV), a hantavirus responsible for one of the most frequently occurring hantaviral diseases, a mild form of HFRS known as nephropathia epidemica (NE) (Heyman et al, 2011; Linderholm and Elgh, 2001). This work provides the first molecular-level insights into antibody-mediated targeting of the antigenic hantaviral surface
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