Vulnerability found in viral replication opens new doors to antiviral drug research

Getting a virus is a major bummer. Your joints ache, you’re constantly sniffly, you might

get a fever and you just feel tired.

Even worse than the physical symptoms is the fact that your body helps the virus

survive and even thrive. In order to develop and affect your body’s functions, viral cells

introduce their genetic material into your cells and take over the cell’s machinery. The virus uses this machinery to help itself reproduce and infect more of your cells, leaving you feeling even more sick. Most of the time, when you go treat the virus your immune system is working to fight off, you’re not actually treating the root cause of the virus. You’re only treating the symptoms.

Fortunately, Masaki Nishikiori, a researcher in the Morgridge Institute for Research Virology Team led by Paul Ahlquist, and his research specialist Zach Coleman have made an unprecedented discovery that could lead to the creation of a general antiviral drug for a specific class of (+) RNA viruses.

The Ahlquist group discovered an unexpected chemical reaction that occurs during the viral takeover of a host cell. Viral proteins cause the creation of pores in a cell’s organelle that allow for communication across its membrane; this organellar membrane was originally believed to be completely solid and so it was thought that the organelle itself was not involved in viral replication.

These pores allow for the release of oxidants generated by a specific enzyme, ERO1, from the organelle into the cell’s cytoplasm. The released oxidants allow for the formation of disulfide bonds between viral proteins, leading to the activation of virus proteins in the host cell.

In the regards to the importance of this finding, Nishikiori said, “Such [a] reaction does not occur in the cytoplasm where (+) RNA viruses replicate their RNA genomes. This finding lets us focus on the organellar lumen and its unexpected roles.”

Though most virologists believe that the cytoplasm is most important when it comes to researching viral replication, this discovery demonstrates that the organelle inside the cytoplasm contributes just as much to the survival and development of the virus and is definitely worth studying.

Coleman said that all in all, this genome replication process is central to virus propagation and survival. If this process can be inhibited, the virus’s demise will come quickly after. For this reason, the pores created in the organelle are an extremely valuable target for drugs; if they can be blocked, oxidants generated by the ERO1 enzyme will not be able to pass through and virus-host communication will be prevented, causing the virus’s replication to halt.

At the moment, though, this treatment possibility is limited to a certain superfamily of (+) RNA viruses — the alphavirus superfamily. While it is known that the pores created by alphaviruses are channels for oxidants, the function of the pores formed by (+) RNA viruses in other super-families is unknown. Nishikiori said that if the function of the pore is unknown, so are the consequences, making the creation of an effective drug not an option. But his study also sheds light on the possibility that other virus superfamily members might employ a similar virus replication strategy which could be, in turn, used to conquer various (+) RNA viruses by their “pore blocker” strategy.

One example of an alphavirus is the Chikungunya virus, which is spread by insects. Outbreaks are being seen in Africa, Asia, Brazil and even Florida and the virus is making its way further into the United States, Coleman and Nishikiori said. Symptoms include fever and debilitating joint pain that can last for weeks or even months. There is no commercial vaccine or specific antiviral treatment for Chikungunya and when patients are treated it usually involves relieving symptoms.

Before taking steps toward general antiviral drug research to treat the root cause of viruses like Chikungunya, Coleman said that the goal in the near future will be to “gather more information [about the system so] then we can start figuring out more of a target.” The two will expand their knowledge on this newly-found system and further explore the unexpected roles it might play.

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