Review Article

Evolution of Therapeutic Antibodies, Influenza Virus Biology, Influenza, and Influenza Immunotherapy

Table 2

Functions of influenza virus proteins.

Gene segmentName of proteinFunction(s)

1PB2Basic polymerase recognizes and binds to the cap that the PB1 snatched from the host pre-mRNAs for genome replication

2PB1Basic polymerase with endonuclease activity that can excise cap structure () from the host pre-mRNA for initiation of the viral transcription
PB1-F2Impair the cellular innate immunity by accelerating mitochondrial fragmentation
PB1-N40Maintains the balance of expressions of the PB1 and the PB1-F2

3PAAcidic polymerase which involves in the viral transcription and replication
PA-XPossesses endonuclease activity and contributes to viral growth and virulence and host immune response suppression
PA-N155 and PA-N182Do not have polymerase activity; likely possess important functions in the replication cycle of influenza A virus as virus mutants lacking these proteins replicate more slowly in cell culture and have lower pathogenicity in mice

4HAPlays major role in the early stage of infection by binding with host cell receptors for virus entry (function of the HA1 domain) and viral-endosomal membrane fusion for cytoplasmic entering of the vRNPs (activity of the HA2) for further virus replication in nucleus

5NADigests the sialic acid receptors on the host cell to free the newly formed virus particles for further spread
Cleaves sialic acid in the extracellular matrix to facilitate the HA binding to the cellular receptors at the initial stage of infection
NA also limits viral superinfection of the infected cells

6NPNP encapsidates the viral RNA and binds one molecule each of PB2, PB1, and PA to form RNA-dependent RNA polymerase (RdRp) complex for viral transcription and replication
Later in the infection, NP is bound by M1 which mediates nuclear export of newly produced vRNPs through interacting with nuclear export protein, NEP
It is also possible that NP binds directly host exportin-1/XPO1 and plays an active role in RNPs nuclear export

7MM1: at early stage of infection, M1 releases endocytosed vRNP while the HA molecule undergoes conformational change to expose HA2 peptide that causes host-viral membranes fusion and an exit of the vRNP into cytoplasm for further transport to nucleus where the viral RNA replication takes place
M1 interacts with NEP and NP for transporting newly synthesized vRNPs from nucleus to cytoplasm for further assembly and budding
M1 also prevents the newly formed vRNPs from re-entering the nucleus
M2 forms ion channel at the viral membrane which allows H+ to enter the virion causing vRNP release into cytoplasm for further replication in the nucleus
M2 initiates autophagosome formation at the early stage of infection but blocks autophagosome fusion to lysosome at the late phase which consequently compromises survival of the infected cells for viral fitness
M2 prevents acid-induced conformational change of newly produced HA in trans-Golgi network
At the late stage of the viral infection, M2 is recruited by M1 to virus budding site where the M2 amphipathic helices cause plasma membrane curvature and membrane scission for virion release
M42 can replace the M2 functions in the M2-deprived viruses

8NSNS1 suppresses host immunity, inhibits host protein synthesis and enhances viral translation
NEP mediates nuclear export of the newly synthesized vRNPs
NS3 might involve switching from avian to mammalian hosts, including human, swine and canine populations
NS4, NEG8, and NSP: unknown functions