If cases of the illness worldwide and news reports are any indication, the H5N1 avian flu virus could be mankind’s next greatest threat. But what is this killer, and how does it work?
Introducing the Influenza Virus
The influenza virus, like all of its viral cousins, is a shell of protein and lipid protecting a nucleic acid core. In, addition to these general features, it has characteristics typical to the orthomyoxoviridae family to which it belongs, including a complicated structure of plasma membrane derived from the host cell enveloping sequential protein shells and, finally the virus’ RNA genome (remember, as we discussed in connection with HIV, that viruses are classified principally by whether they have DNA or RNA genomes, how they replicate, and whether they have membranes around them derived from a host cell)49.
Inside the innermost protein shell are eight segments of single-strand RNA containing the genetic instructions for making new copies of the virus. Its shape is roughly round but could also be elongated or irregularly shaped. Additionally, the virion surface is composed of an outer layer of protein “spikes”50. There are two different types of these “spikes”: one is the protein hemagglutinin (HA), which allows the virus to stick to a cell and initiate infection while the other is the protein neuraminidase (NA), which cuts up membrane lipids, allowing the virus to enter and exit the cell51. More specifically, NA cuts off an acidic molecule from these lipids called salicylic acid, a molecule to which HA might bind instead of the receptor. Further, this cutting is useful both in allowing the virus to enter the cell (e.g., HA is able to attach to the right place to get in), it also helps the virus escape the cell by allowing newly formed virions to disengage from any salicylic acid molecules that are holding them to the cell52. In other words, the NA cuts the molecular string that keeps a new viral particle tied to the host cell.
Among all influenza viral strains, there exist many isoforms of HA and NA, each varying in amino acid sequence50. However, each individual virus strain possesses only one version of these proteins, and consequently, each influenza strain can be named based on which isoforms are present. For example, the avian flu virus, H5N1, indicates that the virus has HA isoform #5 and NA isoform #1 within its shell. The ability for the virus to evolve different variants of HA and NA on the virion surface helps to elude detection by immune cells. On a larger scale, influenza viruses can also be classified into three other general classes (A, B, C) based on the presence of different internal proteins. The B and C forms mostly infect children, causing mild respiratory illness3.The A form, on the other hand, infects a wide variety of higher organisms including birds and mammals, causing more serious illnesses and the potential for epidemics.
Sticky Tabs for Infiltration
Like HIV and the smallpox virus, the influenza virus recognizes particular receptor molecules on the outside of a human cell. In this case, the appropriate receptors are usually found in the cells of the respiratory tract such as the epithelial cell lining of the throat, bronchial tubes, and trachea. The availability and identity of the receptors accounts for why some viruses infect particular species better than others. For example, a chicken has different receptor molecules on the surface of its cells than a human, and the viral HA proteins usually stick more strongly to the receptor of one species than another. The cases of avian flu in which the virus jumped from birds to humans can be explained by viral mutations in the composition of the virus’ outer coat, resulting in “stickier” virions that now bind to human cells53. There has also been evidence that the avian flu virus is more difficult to transmit between humans because only human cells deep within the respiratory tract have the necessary receptors to the stick to the virus54.
How does this interaction between receptor and viral HA work? To explain this, it’s helpful to remember what receptors normally do, which is recognize molecules outside the cell. The amino acid sequence of a given receptor determines its three dimensional structure, which subsequently only pairs with a specific target molecule. 
When it recognizes its target molecule, the receptor sets off a cascade of secondary chemical events inside the cell with widely varying results.
One possible result is receptor endocytosis, a process that allows the bound virus to enter a cell. Once the outer shell of the flu virus latches on to one of these anchor receptors, it is engulfed by the cell50,55. Inside this membrane pocket, the virus fuses with the surrounding lipid and slips through this thin barrier into the cell’s cytoplasm with the help of the protein M2 found in the protein shell of the virus, which forms a proton/ion permeable channel through the plasma membrane around the virus and consequently lowering the pH inside the endosome by admitting protons51,56,57. Here – in an environment that does not immediately destroy fragile RNA – the outer shell cracks open, allowing the viral genome to initiate propagation within the host cell57.
Reverse Messaging:
Once inside the cell, the viral RNA moves into the nucleus58. Here, the viral RNA is replicated by the notoriously error-prone RNA polymerase, making each successive generation slightly different than its predecessor (discussed further below)59. Unlike HIV, the viral RNA does not integrate within the host’s genome, so infections are acute rather than chronic. When messenger RNAs generated from the viral genome in the nucleus pass into the cytoplasm, the viral proteins can then be synthesized using the cell’s own ribosomes or protein-making machinery60. Ultimately, the cell will be overwhelmed by the number of viruses inside it and die.
Comprehension Questions:
1. What part of the influenza virus is responsible for sticking to its host cell membrane?
2. How does the virus alter the pH inside the endosome containing it?
3. What nucleic acid is the influenza genome made from?
