SMITH-VIKOS: Flu virus ‘tells time’ to cause infection

The flu virus has been spreading across the United States this winter and continues to hospitalize thousands of people.

Many individuals still remain unvaccinated in the wake of this outbreak, but scientists have discovered new information regarding influenza that could improve current vaccine technologies and provide alternatives to anti-viral drugs.

According to researchers at the Icahn School of Medicine at Mount Sinai in New York, the flu virus has an “internal clock,” which helps the virus to determine the exact amount of time it should remain in a human cell to cause infection. Study leader Benjamin tenOever and colleagues have found a way to manipulate this internal clock to prevent the virus from multiplying inside human cells and ultimately transmitting itself from person to person.

Scientists already knew that the flu has a weapon — an abundant protein called Non-Structural Protein 1 (NS1), which is used to disarm the cell during infection. Mt. Sinai researchers observed that even a reduced amount of the NS1 protein still allowed the virus to stop the cell’s defense against it. Professor tenOever hypothesized that influenza produces large quantities of NS1 because its production is coupled with the process of creating another protein, Nuclear Export Protein (NEP), which might actually be the main protein the virus needs to infect cells.

The researchers designed a new virus that produced much more NEP, and they saw that the virus enters the cell and goes into the nucleus to make copies of itself as it should. However, rather than taking the normal eight hours to make millions of copies of itself and then move to the next cell, the virus was prematurely leaving the cell after only two to three hours. This did not provide the virus enough time to get all the necessary resources in place to elicit an infection. The scientists then took the opposite approach and designed a virus that produced very low quantities of NEP. Because NEP was accumulating too slowly, the virus now took even longer to leave the cell — instead of getting ready to leave after eight hours, it took 10 to 12 hours. This was just enough time for the immune response to kick in and destroy the virus.

So, the flu virus has a mechanism to “tell time” in order to make enough copies of itself inside each cell to cause infection before getting caught by the immune system. If the virus wants to know how long it has been in the cell, it just needs to know the concentration of the NEP protein. Once NEP reaches a certain concentration, the virus knows it’s time to leave, and NEP helps the flu’s exit strategy by exporting the virus from the nucleus to the cytoplasm to leave the cell — hence the name “Nuclear Export Protein.”

Although the applications of this research may be years away from clinical trials, there is still much excitement to immediately begin developing new technologies. Scientists will use these findings to design alternatives to anti-viral drugs like Tamiflu.

Researchers have said that the previously disregarded NEP protein, which acts as a “viral clock signal,” is actually an important drug target. Creating a drug that would artificially make the virus tell time too slowly would allow the virus to linger in the cell long enough for the immune system to respond.

This research will also be important for producing influenza vaccines. Currently, individuals can either receive a shot or a nasal spray vaccine. While the nasal spray vaccine is thought to work better, it is only FDA-approved for people ages 2–49 because the spray delivers a live but weakened virus that can still cause symptoms in immunocompromised individuals.

If a spray vaccine instead delivered a virus with a defective “clock,” even compromised immune systems, such as those found in very young and very elderly individuals, would be able to destroy the virus since their bodies would have enough time to prevent infection symptoms, according to tenOever. The flu has been a particularly infectious strain this winter and has already resulted in a full-on epidemic along the East Coast. However, the flu vaccine is very accurate this year — the vaccine always contains two strains of the virus, H1N1 and H3N2, and this winter’s predominant circulating strain is H3N2, which tends to be much less variable and easier to predict for developing a vaccine.

The problem remains that not enough people are getting vaccinated, making it all too easy for the H3N2 strain to circle through the population. Vaccinated individuals may still develop some symptoms, but these will certainly be less severe than if they were not vaccinated. With reports from the Centers for Disease Control and Prevention of under 50 percent of Americans getting vaccinated this season, protecting oneself from the flu should no longer be a personal choice. Communities need to take the initiative to provide accessible options for everyone to receive a flu vaccination.

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