Contributed by Guest Blogger: M. Steinschneider ’14
The influenza virus’s unique, 8 fragments genomic structure makes the virus quite fast to evolve, and therefore very difficult to vaccinate against. New techniques for protection against the virus are thus desirable. A 2008 study by Dimmock et. al has identified a naturally existing sequence of defective influenza A RNA, named 244 RNA. Their study suggests that defective, 244 RNA viruses protect against H1N1, as well as other strains of the influenza A virus. This holds interesting implications for the prevention and treatment of influenza, perhaps providing an alternative to vaccination.
Experiments conducted in the study support Dommick’s conclusion that the 244 RNA virus protects against functional strains of influenza A. For instance, a group infected with the 244 RNA carrying virus was then infected with a human H3N2 strain, and then compared to a control group that was infected with the same H3N2, but not given the protecting virus. While the control group lost weight and demonstrated other signs of illness, the group given the protecting virus remained healthy.
The mechanism suggested by Dimmock et. al is that the 244 RNA protecting virus infects cells in the respiratory tract, an important target for the influenza Virus. Since influenza A viruses infecting the same cell are capable of swapping genetic information, due to their unique genomic arrangement, other influenza viruses introduced into the host will take on the defective RNA. The packaging process does not favor the functioning RNA sequence over the defective 244 RNA, so the 244 RNA is favored if it proportionally outweighs the functional RNA sequence.
Although this seems highly promising for fighting influenza, it does lead to several questions. For instance, is it possible that the protecting virus could mutate at some point? If this were to happen, it may cease to be benign. There is also the chance that Influenza A may mutate to have a mechanism for favoring the correct RNA during genetic swapping. Still, 244 RNA seems to be an effective and creative approach to protecting against influenza, by turning the virus’s strength (genetic flexibility in multi-infected cells) against it.
The flu comes back year after year, and every season we get vaccinated (well, some of us anyway). Why do we need to keep getting a new shot for the flu while for others, like measles, we got way back in childhood and are done with it for the rest of our lives?
Our immune response to influenza involves production of antibodies, large proteins that specifically bind to the virus and help clear it out or neutralize it. It seems like the key to influenza immunity is neutralizing antibodies, antibodies that bind to the virion and prevent it from attaching to the host cell. You can imagine this large protein just being physically in the way, preventing the virus from binding the host receptor. The immune response that develops from natural exposure or vaccination generates neutralizing antibodies to HA, a viral envelope protein that is necessary for attachment to the host. I’ve mentioned HA in a previous post about influenza. The problem is that last season’s neutralizing antibodies dont bind to this season’s virus. Although it may be nearly identical to the virus from a past season, the new strain’s HA is slightly different, and those differences are enough to evade existing neutralizing antibodies.
Now a new approach to vaccination has shown that it may be possible to develop a vaccine that illicits broadly neutralizing antibodies, that is, antibodies that will protect against influenza strains with slightly different HAs. They used a prime/boost approach, in which a DNA vaccine was used to induce an initial response against HA, and then boosted with a regular seasonal flu vaccine. The only difference between this and what is currently done is the addition of the DNA vaccine. However the response seems quite different. Neutralizing antibodies were generated that can neutralize a variety of different influenza viruses. It seems the vaccine induced antibodies to a different part of HA. Antibodies are so specific, the dont recognize the whole HA, but rather discrete parts of it. The part recognized by these antibodies, called the stem, is highly conserved, meaning it doesnt change season to season.
This raises many interesting questions and possibilities. Could we soon have a universal vaccine that will protect us for life or at least for many years? Why did the change in vaccine regimen induce antibodies to a different part of HA? Why does the current vaccine or natural exposure fail to develop antibidies to the conserved portion of HA? Will the conserved portion of HA eventually change too, if sufficient selective pressure is applied through mass vaccination?
The 1918 influenza pandemic (the “Spanish Flu”), by some estimates, killed as many as 100 million people in a very short period of time. The 2009 “Swine Flu” pandemic didnt kill so many, but it spread rapidly and widely across the globe. Despite that difference, it turns out the two viruses responsible for these pandemics have some important similarities.
Influenza virus has a protein on the surface called hemagglutinin, or HA, which is used to attach to host cells, allowing the virus to then enter and replicate. HAs change rapidly, which is partly why influenza keeps coming back. When HA changes, your antibodies dont recognize it so well, so you get sick again. It turns out that the HAs of 2009 and 1918 are similar on both the sequence and structure level. There is a small patch on the HA protein that is 95% identical between 1918 and 2009 but only 70% identical to seasonal strains. Looking only at the 3D structure, among all influenza HAs, the 2009 HA is most similar to the 1918 HA. The 1918 and 2009 HAs also lack glycosylation at the tip, while seasonal influenza viruses HAs are sugary.
Why is that interesting? An unusual pattern was noted in the 2009 pandemic: elderly people were not as affected as younger people, the reverse of what is usually seen with influenza. It was proposed that perhaps some people still had immunity to the 1918 virus, which continued to circulate for many years after 1918, and that immunity was cross-protective. A recent study shows that this indeed seems to be the case. Mice immunized with the 1918 virus are protected against the 2009 virus. The converse is also true: if you immunize mice with the 2009 virus, they are protected against the 1918 virus. That’s pretty impressive when you consider that one season’s vaccine might not protect you from next season’s virus. It seems the immune system cant really tell the difference between these viruses. Note that it also tells us how long immunity can last! The next question is, how and why has this HA structure come back?