90 Virology of Human Influenza

The activity of the M2 protein is inhibited by amantadine, rimantadine and related substances.

Possible function of NS1

Human messenger RNA carries a poly-A tail at the 5' end. NS1, with a molecular weight of 26,000, and forms a dimer that inhibits the export of poly-A containing mRNA molecules from the nucleus, thus giving preference to viral RNA which is transported to the ribosome and translated. NS1 might also inhibit splicing of premRNA. In addition, NS1 is probably able to suppress the interferon response in the virus-infected cell leading to unimpaired virus production.

Possible function of NS2

NS2 is a small molecule with a molecular weight of 11,000. In the particle it might be bound to M1 protein. Its function is believed to facilitate the transport of newly synthesised RNPs from the nucleus to the cytoplasm to accelerate virus production.

Replication cycle

Adsorption of the virus

The influenza virus binds to the cell surface by fixing the outer top of the HA to the sialic acid of a cell’s glycoproteins and glycolipids. The sialic acid linkage to the penultimate galactose, either alpha 2,3 (in birds) or alpha 2,6 (in humans), determines host specificity. Since sialic acid-presenting carbohydrates are present on several cells of the organism, the binding capacity of the HA explains why multiple cell types in an organism may be infected.

Entry of the virus

After attachment, the virus is taken up by the cell via a clathrin-coated receptormediated endocytosis process. When internalised, the clathrin molecules are liberated and the vesicle harbouring the whole virus fuses with endosomes. The contents of the vesicle are usually digested through a stepwise lowering of the pH within the phagosome.

Uncoating of the virus

When a certain level is reached, the lowering of the pH is stopped by the action of the M2 protein which induces the partial liberation of the fusion peptide of the HA. This allows the fusion of the HA with the membrane of the vesicle and liberation of the ribonucleoproteins (RNPs) into the cytoplasm, as described above. The ion influx from the endosome to the virus particle leads to disconnection of the different viral proteins; M1-protein aggregation is disrupted and RNPs no longer adhere to the M1-protein complex. Uncoating is completed within 20-30 min of virus attachment.