Influenza Virus: The Flu, Genetic Drift & Shift, Neuraminidase & Hemagglutinin

Influenza Virus causes the Flu. Influenza should not be confused with the bacteria Haemophilus influenza (AKA H Flu). The influenza virus causes a very common acute respiratory tract infection. Clinically it presents as fatigue, rhinorrhea (runny nose), myalgia (muscle pain), fever, cough/sore throat, and headache. There are laboratory tests available, but the flu is almost always a clinical diagnosis. It is spread mainly through air via respiratory droplets. Symptoms usually begin a couple days after being infected, but some patients remain asymptomatic. Most people will recover completely within 1 to 2 weeks. Sometimes it is difficult to tell the difference between the flu and the common cold which is caused by a different virus. There is a lot of overlap in symptoms between the two, but the flu is usually more severe and lasts longer. A high fever and body aches are also more often associated with the flu.

Question stems usually mention the time of year as a majority of flu cases within the US occur during between November and April. There is not a definitive answer as to why the flu occurs in the winter, but it could just be due to people being indoors and in close proximity more often. Other potential contributing factors include increased travel during the holidays and drier air. The question stem may also give you a big clue by mentioning that the patient is unvaccinated or that they had a recent sick contact (AKA a family member has the flu).

Usually, the flu is self-limited and only supportive treatment with over the counter medications is needed. Antiviral treatment is recommended for patients at high risk of complications. It should be started within the first 2 days of symptom onset. Antiviral options include neuraminidase inhibitors such as Oseltamivir (trade name Tamiflu) & Zanamivir that inhibit virus release.

The general public thinks of the flu as a relatively mild infection. However, serious complications and even death are possible especially in high risk populations. There are hundreds of thousands of deaths worldwide attributed to the flu each year. The infection can spread into the lower respiratory tract and cause viral pneumonia or weaken the immune system leading to a secondary bacterial infection (AKA “superinfection”). Children, pregnant women, and the elderly have a higher risk for complications. Patients with a history of smoking, COPD, Asthma, immunosuppression, and other health conditions also have increased risk.

There is of course a yearly Influenza Vaccine (AKA Flu Shot) that you should be very familiar with. As medical personnel you are probably required to get it every year by your school or healthcare organization. The vaccine is recommended for nearly everyone, but is especially important in high risk individuals. It is available in inactivated and live attenuated forms. Since it takes a lot of time to make millions of vaccines, predictions have to be made in advance about what strains of the virus will be most common. Unfortunately, sometimes these predictions end up being partially wrong. This is why in certain years the vaccine isn’t as effective as others. Even in the best of years the vaccine isn’t 100% effective as there is a lot of variety among influenza viruses. This is one of the reasons some patients believe “the flu vaccine doesn’t work.” Even worse there is widespread belief that “you can get the flu from the flu vaccine” which is highly unlikely. Part of this belief may be related to the fact that it takes a couple weeks after getting the vaccine for it to “kick in.” Therefore, some people will get the infection before the vaccine starts working and claim the vaccine doesn’t work. Alternatively patients may get another virus, such as the common cold, after getting the vaccine and mistakenly think they got the flu. Some patients also have a mild reaction after receiving the vaccine that includes mild flu like symptoms. More serious allergic reactions to the vaccine are possible and vaccine is contraindicated in those with severe egg allergy.

The influenza virus is an enveloped virus with a single stranded RNA genome. Interestingly the RNA is split into about 8 separate segments similar to the Rotavirus. The segmented nature of these genomes allows for RNA segments to be exchanged between viruses, a process known as Reassortment. In this case 2 different influenza viruses infect a single host and a mixture of their genome segments can create a new virus with much higher virulence. This sudden change in the virus genome is called Genetic Shift and is responsible for pandemics (global disease outbreaks). Typically this involves a human strain of the virus gaining a completely new surface antigen from a strain of the virus which typically resides in another species. This new surface antigen means that the human immune system can no longer detect the virus based on “experience” gained from previous encounters with the influenza virus. A recent example includes the “Swine Flu” pandemic in 2009 which was caused by a combination of genomes from swine, avian and human strains of the virus.

There is also a more gradual process for the influenza virus to adapt called Genetic Drift. In this process mutations slowly accumulate in the viral genome. This leads to an increasing diversity within the virus. In particular mutations that affect the surface antigens of the virus are important. Some of these mutations will give the virus a survival advantage that allows it to cause epidemics (AKA the seasonal flu outbreaks that are mostly restricted to individual countries). However, since the new version of the virus still resembles strains from previous epidemics part of the population remains immune.

Genetic Drift Genetic Shift

Neurominidase Hemagglutinin

There are 3 types of influenza virus; types A, B, and C. Types A and B cause annual epidemics while type C not nearly as common and often causes mild symptoms. Type A is found in many species and therefore antigenic shift is possible and pandemics are more likely. Type B is only found in humans and therefore slower antigenic drift changes lead to pandemics less often.

Hemagglutinin/Haemagglutinin (HA) and neuraminidase (NA) are glycoproteins on the outside of the Influenza virus envelope. Hemaglutinin is important for the virus to be able to bind to target cells and insert its viral genome. Neuraminidase is important during the process of the virus releasing offspring from the infected cell. There are many subtypes of hemagglutinin and neuraminidase, but only H1-3 and N1-2 are found commonly in humans. You have likely heard of subtypes of the Influenza A virus such as H1N1 which includes hemagglutinin 1 and neuraminidase 1. This is the subtype of the virus that caused the Spanish Flu pandemic in 1918 and the Swine Flu pandemic in 2009. Alternatively, Influenza Type A subtype H5N1, more commonly referred to as “Bird Flu,” was the center of media attention in 2008.

Since HA & NA are so integral to the function of the virus, they are targets for preventing and treating influenza. The body creates antibodies against Hemagluttinin. These antibodies bind to HA thereby inhibiting the attachment of the virus to the surface of host cells. Individuals with antibodies against certain types of HA are immune to that subtype of the virus. Neuraminidase Inhibitors are a class of antiviral drugs that prevent the release of viruses by inhibiting the action of the neuraminidase enzyme. Examples include Zanamivir & Oseltamivir (Tamiflu). If the patient is diagnosed within 48 hours of the onset of symptoms one of these medications can be added to the treatment regimen to lessen the severity and decrease complications. However, antipyretics and analgesia are usually sufficient for treatment.

Pictures Used:

  • Derivative of “3D Influenza virus” by NIH available at via Public Domain
  • “Virus Replication large” by YK Times available at via Creative Commons Attribution-Share Alike 3.0 Unported

Free USMLE Step1 Videos