Convergent #Structures Illuminate #Features for #Germline #Antibody Binding and Pan- #Lassa Virus Neutralization (Cell, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Cell. 2019 Aug 8;178(4):1004-1015.e14. doi: 10.1016/j.cell.2019.07.020.

Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization.

Hastie KM1, Cross RW2, Harkins SS1, Zandonatti MA1, Koval AP3, Heinrich ML3, Rowland MM3, Robinson JE4, Geisbert TW2, Garry RF5, Branco LM3, Saphire EO6.

Author information: 1 La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. 2 University of Texas Medical Branch, Galveston National Laboratory, Galveston, TX, USA. 3 Zalgen Labs, Germantown, MD, USA. 4 Department of Pediatrics, School of Medicine, Tulane University, New Orleans, LA, USA. 5 Zalgen Labs, Germantown, MD, USA; Department of Microbiology and Immunology, Tulane University, New Orleans, LA, USA. 6 La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: erica@lji.org.

 

Abstract

Lassa virus (LASV) causes hemorrhagic fever and is endemic in West Africa. Protective antibody responses primarily target the LASV surface glycoprotein (GPC), and GPC-B competition group antibodies often show potent neutralizing activity in humans. However, which features confer potent and broadly neutralizing antibody responses is unclear. Here, we compared three crystal structures of LASV GPC complexed with GPC-B antibodies of varying neutralization potency. Each GPC-B antibody recognized an overlapping epitope involved in binding of two adjacent GPC monomers and preserved the prefusion trimeric conformation. Differences among GPC-antibody interactions highlighted specific residues that enhance neutralization. Using structure-guided amino acid substitutions, we increased the neutralization potency and breadth of these antibodies to include all major LASV lineages. The ability to define antibody residues that allow potent and broad neutralizing activity, together with findings from analyses of inferred germline precursors, is critical to develop potent therapeutics and for vaccine design and assessment.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS: Lassa virus; antibody; arenavirus; germline; neutralization; protein engineering; structural biology

PMID: 31398326 DOI: 10.1016/j.cell.2019.07.020

Keywords: Arenavirus; Lassa fever.

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Giuseppe Michieli

I am an Italian blogger, active since 2005 with main focus on emerging infectious diseases such as avian influenza, SARS, antibiotics resistance, and many other global Health issues. Other fields of interest are: climate change, global warming, geological and biological sciences. My activity consists mainly in collection and analysis of news, public services updates, confronting sources and making decision about what are the 'signals' of an impending crisis (an outbreak, for example). When a signal is detected, I follow traces during the entire course of an event. I started in 2005 my blog ''A TIME'S MEMORY'', now with more than 40,000 posts and 3 millions of web interactions. Subsequently I added an Italian Language blog, then discontinued because of very low traffic and interest. I contributed for seven years to a public forum (FluTrackers.com) in the midst of the Ebola epidemic in West Africa in 2014, I left the site to continue alone my data tracking job.