and various other USAMRIID authors was supported with the Army Infectious Disease Analysis Program under task amount MI210048. Gn. Identifying the antigenic sites for neutralizing antibodies will donate to further healing advancement for hantavirus-related illnesses and inform the look of brand-new broadly defensive hantavirus vaccines. Analysis organism:Viruses == Introduction == Hantaviruses are emerging zoonotic pathogens that are endemic worldwide and classified into two categories based on the geographic distribution of their reservoir hosts and pathogenesis in humans (Jonsson et al., 2010). Almost 60 virus species have been identified in rodents or shrews, and over 20 species cause disease in humans (Laenen et al., 2019). Old World hantaviruses, including Hantaan virus (HTNV), Puumala virus (PUUV), Dobrava -Belgrade virus (DOBV), and Seoul virus (SEOV), mainly occur in Eastern Europe and China and cause hemorrhagic fever with renal syndrome (HFRS). New World hantaviruses (NWHs), including Sin Nombre virus (SNV) and Andes TIMP1 virus (ANDV), are endemic in North and South America and cause hantavirus cardiopulmonary syndrome (HCPS). Person-to-person transmission of ANDV has been reported, including in a recent outbreak in Argentina resulting in 34 confirmed cases and 11 fatalities (Martinez et al., 2005;Martnez et al., 2020). There are no current FDA-approved medical countermeasures to prevent or treat hantavirus-related disease. The viral glycoproteins, designated Gn and Gc, form a hetero-tetrameric spike on the surface of the hantavirus virion and facilitate attachment and entry. Previous studies have reported crystal structures for the Gn (Li et al., 2016;Rissanen et al., 2017) and Gc (Guardado-Calvo et al., 2016;Willensky et al., 2016) ectodomains of PUUV and HTNV, and recent work has described the molecular Azasetron HCl organization of Gn/Gc on the virion surface (Serris et al., 2020). Gc is a class II fusion protein and undergoes conformational changes triggered by low pH to mediate the fusion of the viral and host endosomal membranes. Gn is proposed to play a role in receptor attachment and stabilize and prevent the premature fusogenic triggering of Gc (Mittler et al., 2019;Bignon et al., 2019). Structural studies have identified a capping loop on Gn that shields the fusion loop Azasetron HCl on Gc, and the glycoprotein complex is thought to undergo dynamic rearrangements between a Azasetron HCl closed (or capped) and open (or uncapped) form of the spike (Serris et al., 2020;Bignon et al., 2019). Recent efforts have identified features of the molecular basis of neutralization by some antibodies targeting HTNV Gn (Rissanen et al., 2021) or PUUV Gc (Rissanen et al., 2020). A rabbit-derived antibody, HTN-Gn1, targets domain A on Gn and overlaps with the putative binding sites for other murine-derived HTNV (Arikawa et al., 1992) and ANDV mAbs (Duehr et al., 2020). An antibody isolated from a bank vole, P-4G2, targets a site spanning domain I and II on Gc that is occluded Azasetron HCl in the post-fusion trimeric form, suggesting that the antibody may neutralize through blocking conformational changes required for fusion (Willensky et al., 2016;Rissanen et al., 2020). Although mAb P-4G2 neutralizes PUUV and ANDV, this activity has only been tested in pseudovirus neutralization assays, and it is unknown if the antigenic site on Gc is occluded on the surface of the authentic virus. Also, these antibodies were not derived from human B cells and were not induced by Azasetron HCl natural infection, but rather were elicited following inoculation of animals immunization with recombinant protein, recombinant VSV constructs, or virus-infected tissues. It is unclear what sites are accessible to antibodies during a natural infection, and if human antibodies target antigenic sites that differ from those recognized by rodents. The.