Mechanism of Infection and Replication

Like many viruses the influenza virus behaves as a freeloader, utilising the energy and machinery of the host organism in order to replicate and survive. Infection, replication and release occur in the series of stages described below:

 Entry and Uncoating

1. The airborne influenza virus enters the respiratory tract and binds through its hemagglutinin glycoprotein to a sialic acid receptor on the host cell plasma membrane.

2. Once attached to the receptor, the virus is internalised by clathrin mediated endocytosis into the endosome. 

3. The pH of this internalised vesicle/ endosome acidifies and causes hemagglutinin to undergo a conformational change, revealing a hydrophobic fusion peptide. Once this peptide is inserted into the endosomal membrane, fusion of the viral capsid with the endosome is triggered, uncoating and releasing the viral ribonucleoproteins into the cytosol. The M2 ion channel plays a role in this pH dependent fusion process and is important as the capsid is too large to pass through the nuclear pore complex.

4. The nucleoproteins associated with the viral RNA contain signal peptides which direct the viral ribonucleoproteins (vRNPs) through the nuclear pores and into the nucleus. 

Viral Replication and Transcription

5. Once in the nucleus the viral negative sense RNA acts as template for complimentary positive sense strands of messenger RNA (mRNA) and copy RNA (cRNA) synthesis. The multiple complimentary cRNAs act as a template to assemble as many copies of negative sense viral RNA, identical in amino acid sequence to the parent genome. The mRNA on the other hand are capped, polyadenylated and exported into the cytosol where they are translated into viral proteins such as RNA polymerase, M1, M2, NA and HA. Some of these proteins are then imported back into the nucleus for viral assembly.

6.The newly synthesized proteins associate with the many copies of replicated viral RNA to form ribonucleoproteins. These vRNPs are then trafficked to the host cell plasma membrane.

Assembly and Release

 7. The M1 protein binds to both the vRNPs and the host cell plasma membrane and forms the capsid underneath.

8. The glycoprotein neuraminidase cleaves sialic acid receptors on the surface of the plasma membrane to enable release and the new viruses bud off taking a layer of host cell plasma membrane with them (envelope).

9. The newly replicated viruses may then infect other host cells in the respiratory tract, repeating the cycle and exponentially increasing the number of viruses in the host organism.

Influenza Virus Replication Cycle. Image modified from  https://commons.wikimedia.org/wiki/File:Virus_Replication_large.svg under the terms of the GNU Free Documentation License.