A Computationally Designed Hemagglutinin Stem-Binding Protein Provides In Vivo Protection from Influenza Independent of a Host Immune Response

PLoS Pathogens

Travis Nieusma¹  Ian A. Wilson¹  Andrew B. Ward¹  Peter S. Lee¹  Merika Treants Koday²  Hannah Kalinoski²  Donald F. Smee³  David Baker³  Deborah Heydenburg Fuller⁴  Lauren Carter⁴  Lance Stewart⁴  Jorgen Nelson⁴  Aaron Chevalier⁴  Ashley Dagley⁵  Michael Koday⁶ 

[1] Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America;Department of Microbiology, University of Washington, Seattle, Washington, United States of America;Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, United States of America;Institute for Protein Design, Department of Biochemistry, University of Washington, Seattle, Washington, United States of America;Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America;Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America

关键词: Influenza;    Cytokines;    Influenza viruses;    Inflammation;    H1N1;    Mouse models;    Immune response;    Prophylaxis;   

DOI  :  10.1371/journal.ppat.1005409

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Broadly neutralizing antibodies targeting a highly conserved region in the hemagglutinin (HA) stem protect against influenza infection. Here, we investigate the protective efficacy of a protein (HB36.6) computationally designed to bind with high affinity to the same region in the HA stem. We show that intranasal delivery of HB36.6 affords protection in mice lethally challenged with diverse strains of influenza independent of Fc-mediated effector functions or a host antiviral immune response. This designed protein prevents infection when given as a single dose of 6.0 mg/kg up to 48 hours before viral challenge and significantly reduces disease when administered as a daily therapeutic after challenge. A single dose of 10.0 mg/kg HB36.6 administered 1-day post-challenge resulted in substantially better protection than 10 doses of oseltamivir administered twice daily for 5 days. Thus, binding of HB36.6 to the influenza HA stem region alone, independent of a host response, is sufficient to reduce viral infection and replication in vivo. These studies demonstrate the potential of computationally designed binding proteins as a new class of antivirals for influenza.

【 授权许可】

CC BY