title: Inhibition of influenza virus infection and hemagglutinin cleavage by the protease inhibitor HAI-2.
abstract: Influenza virus remains a significant concern to public health, with the continued potential for a high fatality pandemic. Vaccination and antiviral therapeutics are effective measures to circumvent influenza virus infection, however, multiple strains have emerged that are resistant to the antiviral therapeutics currently on the market. With this considered, investigation of alternative antiviral therapeutics is being conducted. One such approach is to inhibit cleavage activation of the influenza virus hemagglutinin (HA), which is an essential step in the viral replication cycle that permits viral-endosome fusion. Therefore, targeting trypsin-like, host proteases responsible for HA cleavage in vivo may prove to be an effective therapeutic. Hepatocyte growth factor activator inhibitor 2 (HAI-2) is naturally expressed in the respiratory tract and is a potent inhibitor of trypsin-like serine proteases, some of which have been determined to cleave HA. In this study, we demonstrate that HAI-2 is an effective inhibitor of cleavage of HA from the human-adapted H1 and H3 subtypes. HAI-2 inhibited influenza virus H1N1 infection in cell culture, and HAI-2 administration showed protection in a mouse model of influenza. HAI-2 has the potential to be an effective, alternative antiviral therapeutic for influenza.
authors: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
authors: Brian S
authors: BS
authors: Hamilton
authors: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
authors: Changik
authors: C
authors: Chung
authors: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
authors: Soreen Y
authors: SY
authors: Cyphers
authors: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
authors: Vera D
authors: VD
authors: Rinaldi
authors: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA.
authors: Valerie C
authors: VC
authors: Marcano
authors: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853, USA. Electronic address: grw7@cornell.edu.
authors: Gary R
authors: GR
authors: Whittaker
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D005260:Female; D057809:HEK293 Cells; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000378:metabolism; D053122:Influenza A Virus, H3N2 Subtype / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D014771:Virion / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D008565:Membrane Proteins; D009842:Oligopeptides; D011994:Recombinant Proteins; C533525:Spint2 protein, mouse; C483468:hemagglutinin, human influenza A virus
keywords: HAI-2; Hemagglutinin; Influenza virus; Protease inhibitor