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PLoS Pathog. 2016 Feb 4;12(2):e1005409. doi: 10.1371/journal.ppat.1005409. eCollection 2016 Feb.

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

Author information

1
Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
2
Institute for Protein Design, Department of Biochemistry, University of Washington, Seattle, Washington, United States of America.
3
Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America.
4
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.
5
Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.
6
Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah, United States of America.
7
Howard Hughes Medical Institute, University of Washington, Seattle, Washington, United States of America.

Abstract

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.

PMID:
26845438
PMCID:
PMC4742065
DOI:
10.1371/journal.ppat.1005409
[Indexed for MEDLINE]
Free PMC Article

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