Flu virus: an example of variability

In this step we will learn about the flu viruses, what is their structure and replication cycle. The genome of these viruses is very unstable, which originates antigenic modifications that sometimes compromise the efficiency of antibodies against infections caused by successive viruses or by different viruses which may circulate at different times. Influenza viruses belong to the family Orthomyxoviridae. They are negative-sense single-stranded RNA viruses, and the genome is divided into 7 or 8 fragments. The complete particle measures between 80 and 120nm, is pleomorphic (rounded or filamentous) and has a lipid envelope.

On the surface of the virus, two different relevant proteins are found: neuraminidase and hemagglutinin, which form “peplomers”, which are spikes 4 to 14nm long, distributed evenly throughout the surface of the virus. There are three types of orthomyxovirus (A, B and C); the pathogenic viruses are A orthomyxovirus.

The eight RNA fragments encode 12 to 17 proteins, depending on the virus. Fragments 1, 2 and 3 encode the polymerase complex, which transcribes a messenger RNA from each fragment of the viral genome. Fragments 4 and 6 encode hemagglutinin and neuraminidase, respectively, which are responsible for binding to and degrading of the cell receptor and penetration into the host cell. The remaining fragments encode nucleoprotein and matrix proteins, that wrap the genetic material of the virus, as well as the non-structural protein, which are involved in the modulation of the replication and blockage of the cell response to infection. The nucleoprotein (NP), the matrix protein (M), the hemagglutinin (HA), the neuraminidase (NA) and the non-structural proteins are antigenic proteins (i.e.

they are related with the immune response in the host). The replication cycle of these viruses begins with the contact between the viral hemagglutinin and the receptors on the surface of the host cell, which is made of sialic acid. After this, the virus penetrates by way of endocytosis. An endosome or vesicle, which surrounds the virus, is formed in the cytoplasm. When it acidifies, it lets the viral RNA leak into the cytoplasm. The viral RNA penetrates into the nucleus through pores in the nuclear membrane to initiate replication and transcription. The polymerase complex transcribes each genomic fragment, copying it hundreds of times, generating messenger RNAs.

The messenger RNA leave the nucleus to be translated and the different proteins synthesized pass through the ribosome complex (endoplasmic reticulum-Golgi apparatus) to mature and line the inside of the cell membrane. Some proteins return to the nucleus to associate with the viral RNA. At the same time, other RNA molecules are transcribed into positive-sense RNAs, which serve as templates to generate many negative-sense RNA molecules. Finally, ribonucleoprotein complexes exit the nucleus and begin assembling into particles, which will be released by budding as new viral progeny. This complex process of viral replication may result in minor variations, which are point mutations in amino acid sequences (such as substitutions, insertions, recombinations).

This phenomenon is called “antigenic drift” and causes that viruses are slightly different from season to season. More important antigenic changes (“antigenic shift”) may also occur. These are major variations which involve genetic exchange among viruses from different animal species, and that may give rise to new viruses or variants which will produce a great immune impact on populations and which could potentially originate pandemics. This is what we will see now. How is a new virus or variant generated? When two different viruses infect the same cell, during the process of replication in the nucleus a “mixture” or recombination of RNA fragments from both viruses happens.

Also, the messenger RNAs leaving the nucleus to generate proteins in the endosomal complex will encode proteins of different origins, which can also join the new genomic RNA. A new virus would assemble combining proteins and RNA from different sources, to give rise to a progeny of new viruses or variants. Almost certainly you understand now how flu epidemics arise, lwhich are the ones that we see every year, and the pandemics, which we rarely see and that involve a mixture of different RNA fragments from different viruses.