Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen

Rissanen, Ilona; Krumm, Stefanie A.; Stass, Robert; Whitaker, Annalis; Voss, James E.; Bruce, Emily A.; Rothenberger, Sylvia; Kunz, Stefan; Burton, Dennis R.; Huiskonen, J.T.; Botten, Jason; Bowden, Thomas A.; Doores, Katie J.

doi:10.1128/mbio.02531-20

Cited by 18 publications

(24 citation statements)

References 95 publications

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“…The preponderance of group I nAbs in our panel, together with recent descriptions of nAbs elicited against HTNV Gn/Gc that recognize overlapping or adjacent sequences in Gn H ( 40 ), suggest that this region of Gn, well-exposed on viral particles, is a major target of the antibody response to Gn/Gc in mammals, although it has not been described in earlier work aimed at identifying neutralizing epitopes ( 41 ). Here, we present new evidence that these mAbs exhibit at least two distinct binding modes, exemplified by ADI-37236 and previously reported mAbs ( 40 ) on the one hand and ADI-42898 on the other. Despite escaping binding and neutralization via similar mutations in the capping loop, ADI-37236 could bind both monomeric Gn H and heterodimeric Gn H /Gc proteins, whereas ADI-42898 could only bind Gn H /Gc (fig.…”

Section: Discussionmentioning

confidence: 71%

Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

et al. 2022

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The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the “capping loop” of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.

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Section: Discussionmentioning

confidence: 71%

Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

et al. 2022

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“…Epitopes are located on the outer surface of Gn and Gc glycoproteins. The crystal structure of the Gn complex with a neutralising antibody showed that the epitope includes positively charged amino acid at residues 83-85 [34]. This epitope can potentially serve as a binding site for a 2O-sulphated tetrasaccharide.…”

Section: Computer Modelling 231 Molecular Docking Of 2o-sulphated Fucooligosaccharide With the Integrin β3 Epitopementioning

confidence: 99%

In Vitro Anti-Orthohantavirus Activity of the High-and Low-Molecular-Weight Fractions of Fucoidan from the Brown Alga Fucus evanescens

et al. 2021

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The Hantaan orthohantavirus (genovariant Amur–AMRV) is a rodent-borne zoonotic virus; it is the causative agent of haemorrhagic fever with renal syndrome in humans. The currently limited therapeutic options require the development of effective anti-orthohantavirus drugs. The ability of native fucoidan from Fucus evanescens (FeF) and its enzymatically prepared high-molecular-weight (FeHMP) and low-molecular-weight (FeLMP) fractions to inhibit different stages of AMRV infection in Vero cells was studied. The structures of derivatives obtained were determined using nuclear magnetic resonance (NMR) spectroscopy. We found that fucoidan and its derivatives exhibited significant antiviral activity by affecting the early stages of the AMRV lifecycle, notably virus attachment and penetration. The FeHMP and FeLMP fractions showed the highest anti-adsorption activity by inhibiting AMRV focus formation, with a selective index (SI) > 110; FeF had an SI of ~70. The FeLMP fraction showed a greater virucidal effect compared with FeF and the FeHMP fraction. It was shown by molecular docking that 2O-sulphated fucotetrasaccharide, a main component of the FeLMP fraction, is able to bind with the AMRV envelope glycoproteins Gn/Gc and with integrin β3 to prevent virus–cell interactions. The relatively small size of these sites of interactions explains the higher anti-AMRV activity of the FeLMP fraction.

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“…SNV-24 bound to Gc domain I, an epitope that is only accessible in the pre-fusion state of Gc and is near the interface between inter-spike Gc heterodimers. P-4G2 (a bank vole-derived mAb) 12 and group II human PUUV mAbs described previously 16 also map to a similar site on Gc. This site has limited accessibility in the full virus lattice structure due to neighboring interspike contacts and may results in the incomplete neutralizing activity to authentic virus we demonstrated by these mAbs previously 18 .…”

Section: Resultsmentioning

confidence: 79%

“…Recent efforts have identified features of the molecular basis of neutralization by some antibodies targeting HTNV Gn 12 or PUUV Gc 13 . A rabbit-derived antibody, HTN-Gn1, targets domain A on Gn and overlaps with the putative binding sites for other murine-derived HTNV 14 and ANDV mAbs 15 .…”

Section: Mainmentioning

confidence: 99%

Antigenic mapping and functional characterization of human New World hantavirus neutralizing antibodies

Engdahl

Binshtein

Brocato

et al. 2022

Preprint

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Hantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While sporadic in North and South America, many infections occur in Europe and Asia, with mortality ranging from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or kidney failure. Additionally, the humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins and conserved neutralizing epitopes. Here, we report antigenic mapping and functional characterization for four neutralizing hantavirus antibodies. The broadly neutralizing antibody SNV-53 targets an interface between Gn/Gc, neutralizes through fusion inhibition and cross-protects against the Old World hantavirus species Hantaan virus when administered pre- or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets domain I of Gc and demonstrates weak neutralizing activity across hantavirus species. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking and protect against hantavirus cardiopulmonary syndrome (HCPS) in animals but target two different antigenic faces on the head domain of Gn. Determining the antigenic sites for neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines.

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Structural Basis for a Neutralizing Antibody Response Elicited by a Recombinant Hantaan Virus Gn Immunogen

Abstract: The spillover of pathogenic hantaviruses from rodent reservoirs into the human population poses a continued threat to human health. Here, we show that a recombinant form of the Hantaan virus (HTNV) surface-displayed glycoprotein, Gn, elicits a neutralizing antibody response in rabbits.

Cited by 18 publications

References 95 publications

Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses

In Vitro Anti-Orthohantavirus Activity of the High-and Low-Molecular-Weight Fractions of Fucoidan from the Brown Alga Fucus evanescens

Antigenic mapping and functional characterization of human New World hantavirus neutralizing antibodies

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