Evolution of Therapeutic Antibodies, Influenza Virus Biology, Influenza, and Influenza Immunotherapy
Table 2
Functions of influenza virus proteins.
Gene segment
Name of protein
Function(s)
1
PB2
Basic polymerase recognizes and binds to the cap that the PB1 snatched from the host pre-mRNAs for genome replication
2
PB1
Basic polymerase with endonuclease activity that can excise cap structure () from the host pre-mRNA for initiation of the viral transcription
PB1-F2
Impair the cellular innate immunity by accelerating mitochondrial fragmentation
PB1-N40
Maintains the balance of expressions of the PB1 and the PB1-F2
3
PA
Acidic polymerase which involves in the viral transcription and replication
PA-X
Possesses endonuclease activity and contributes to viral growth and virulence and host immune response suppression
PA-N155 and PA-N182
Do 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
4
HA
Plays 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
5
NA
Digests 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
6
NP
NP 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
7
M
M1: 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
8
NS
NS1 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