Influenza A virus (IAV): a segmented antisense RNA virus encoding 11 proteins

Viral proteinsLocationFunctionCommentsNovel antiviral therapies tested in clinical studies
HaemagglutininViral envelopeAttachment to sialic acid residues on airway and alveolar epithelium, membrane fusion and viral entryAlternate binding to α-2,3 or -2,6 linked sialic acid contributes to pathogenicity In the human airway, proteolytic cleavage and disease severity is connected to host proteases TMPRSS2 and HAT [25–27] The addition of N-linked glycosylations mask haemagglutinin as an antigenic epitope [28–31] but trigger recognition by C-type lectins [32–34]DAS181 (cleavage of sialic acids), flufirvitide (peptide inhibitor binding to haemagglutinin)
NeuraminadaseViral envelopeEnzymatic cleavage of terminal sialic acid residues from newly formed virions and release of progenyAfter haemagglutinin, neuraminadase is the major antigenic epitope Currently approved therapies for IAV infection (osteltamivir, zanamivir, laninamivir and peramivir) target neuraminadase
Matrix protein-2Viral envelopeProton selective ion channel required for viral entry, assembly and buddingMatrix protein-2 has been suggested to promote apoptosis by inhibition of autophagy [35] and induces degradation of ENaC and CFTR [36, 37] and, therefore, impacts alveolar fluid clearanceAVI-7100 (interference with M segment gene expression)
Matrix protein-1Viral matrixStructural links between the membrane and ribonucleoprotein core
Polymerase proteins: PB1,  PB2 and PARibonucleoprotein coreRNA polymerase complex proteinsThe polymerase subunits have been connected to viral pathogenicity and interact with >300 cellular proteins [38] Mutations can alter replication efficiency; e.g. a single amino acid substitution (E627K) induces higher pathogenicity in the 1918, 1957 and 1968 pandemic IAV strains [39, 40] and is found in circulating H5N1 and H7N9 variantsFavipiravir (nucleoside inhibitor targeting PB1)
Nucleocapsid proteinRibonucleoprotein corePackaging of the viral genome
Nonstructural protein-1Expressed during replication, not part of the mature virionImmune evasionCritical for viral evasion of the host immune response It binds a complex of viral RNA, RIG-1 and TRIM25 to inhibit downstream antiviral signalling [41, 42] It also induces the downregulation of the IFN-α receptor [43] and upregulates inhibitors of JAK/STAT signalling (SOCS1 and SOCS3) [43, 44] During infection, non-structural protein-1 also blocks pro-apoptotic signalling by protein kinase R [45, 46] and prevents the activation of NF-κB [47]
Nonstructural protein-2Expressed during replication, not part of the mature virionExport of viral ribonucleoproteins from the nucleus during viral replication
PB1-F2#Expressed during replicationInduction of host cell apoptosisPB1-F2 increases mitochondrial membrane permeability through interactions with mitochondrial membrane proteins ANT3 and VDAC, to enhance BAK/BAX-mediated cytochrome C release [48–50]
  • The mature virion comprises eight structural proteins; the other three are expressed during viral replication. Haemagglutinin and neuraminidase, required for virus binding and release, respectively, are present in the viral envelope. Together, haemagglutinin and neuraminidase determine the antigenic properties of the virus and are used to define different viral strains, e.g. the H1N1 strain responsible for the 2009 pandemic and the H7N9 strain responsible for a recent outbreak of avian influenza in Asia. Some of the viral proteins represent putative novel targets for antiviral therapy. TMPRSS2: transmembrane protease, serine 2; HAT: human airway trypsin-like protease; ENaC: epithelial sodium channels; CFTR: cystic fibrosis transmembrane conductance regulator; RIG-1: retinoic acid inducible gene-1; IFN: interferon; JAK: janus kinase; STAT: signal transducer and activator of transcription; NF-κB: nuclear factor-κB; VDAC: voltage-dependent anion channels. #: not expressed by all viruses.