1区 · 医学
Article
作者: Gröning, Remigius ; O’Brien, Cecilia M. ; Sidoli, Simone ; Geoghegan, James C. ; Sun, Yan ; Ahlm, Clas ; Strandin, Tomas ; Slough, Megan M. ; Esterman, Emma S. ; Zeitlin, Larry ; Ulrich, Rainer G. ; Keller, Markus ; Florez, Catalina ; Walker, Laura M. ; Bakken, Russel R. ; Serris, Alexandra ; Rappazzo, C. Garrett ; Mittler, Eva ; Forsell, Mattias N.E. ; Chandran, Kartik ; Tynell, Janne ; Dye, John M. ; Abelson, Dafna M. ; Herbert, Andrew S. ; Ye, Chunyan ; Rey, Felix A. ; Haslwanter, Denise ; Bradfute, Steven B. ; Wec, Anna Z. ; Polanco, Laura C. ; Jangra, Rohit K. ; Guardado-Calvo, Pablo
Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus–experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb’s accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic.
