The Role of Viperin in Viral Protection with Dr. Chun-Chieh ‘Jack’ Hsu

The future of cancer treatment is here for many patients, thanks to lifesaving advances in cancer immunotherapy. To bring this future to all patients—and apply our knowledge to emerging threats like the novel SARS-CoV-2 coronavirus that causes COVID-19—Cancer Research Institute scientists are looking at different molecular weapons of the immune system.

Chun-Chieh ‘Jack’ Hsu, PhD, a CRI postdoctoral fellow in the lab of Peter Cresswell, PhD, at Yale University, is investigating a protein named viperin that helps promote the elimination of viral infection and is even found in some cancers. But much about viperin and its mechanisms remains unknown, so he’s exploring how it influences immune responses, which could pave the way for future strategies to protect against both viruses and cancers.

Recently, we spoke with Dr. Hsu to learn more about his progress.

Arthur N. Brodsky, PhD:

Hi Dr. Hsu, hope you are well, and thank you for taking the time to speak with me today. So, your project is looking at a protein called viperin. What exactly does viperin do?

Jack Hsu, PhD:

Viperin is an antiviral protein that’s expressed in human cells during viral infection and acts as one of the frontline defenses against viruses. It was first identified by my fellowship sponsor, Dr. Peter Cresswell, nearly twenty years ago. Since then we have learned a lot about this amazing protein and how it can create an antiviral environment in human cells. As of now, viperin has been shown to inhibit more than twenty different types of viruses, including the human immunodeficiency virus (HIV) that causes AIDS, the influenza virus that causes the flu, and Zika virus, among others.

Arthur N. Brodsky, PhD:

While we are aware of viperin’s overall impact on viruses, we still don’t really know much about its molecular mechanisms. Now, fortunately, we have the tools to characterize its activity more in depth. As part of your project, you want to use these cutting-edge tools to figure out how viperin actually exerts its influence, especially when it comes to the production of new proteins inside infected cells. Have you discovered anything interesting yet that you can share?

Jack Hsu, PhD:

In these 20 years the scientific community has learned a lot about this protein. We know it's a multifunctional antiviral protein with more than one antiviral-related activity. We know it kind of ‘customizes’ its antiviral functions against different viruses. But in my study, I’m looking at its one general antiviral function—and that’s the ability to inhibit different viruses by interfering with cellular protein production. I found that viperin more or less shuts down all protein production in cells. It's not specific for our human proteins versus those of the virus or anything, which told me that it might be a potential antiviral mechanism that works against lots of different viruses.

Arthur N. Brodsky, PhD:

What’s so special about protein production? When you say that viperin shuts down protein production, why would this be helpful against viruses?

Jack Hsu, PhD:

That’s a great question. Viruses need host cells to make their own proteins and make copies of themselves because viruses don't have the ability to make proteins. So all viruses rely on the cells of the host—in our case, human cells—to make viral proteins. That’s why this function of viperin is so important because it limits the production of viral proteins for making new viruses. So far, we have observed this effect in Zika virus and in another called Kunjin virus, which is a subtype of West Nile virus.

Arthur N. Brodsky, PhD:

Did you discover anything about the mechanisms of exactly how viperin does this, how it stops protein production?

Jack Hsu, PhD:

Well, we know viperin is an enzyme that catalyzes the production of a small molecule called ddhCTP. I found that this small molecule is able to inhibit protein production just like viperin, so then I sought to define the upstream and downstream signaling molecules in this pathway to determine how ddhCTP mediates this activity.

Arthur N. Brodsky, PhD:

Now that you have this information, what are your next steps? Where do you plan to take your research from here?

Jack Hsu, PhD:

Right now, we are working on this small molecule because we know it can do the same thing as viperin, at least when it comes to stopping protein production. Moving forward, we want to know if we can use this small molecule to inhibit viral protein production and provide an actual therapy to protect against different viral diseases.

Arthur N. Brodsky, PhD:

Speaking of therapies for the clinic, as you mentioned earlier, viperin has been shown to protect against a variety of viruses. With respect to the current COVID-19 pandemic, has your team turned its focus toward, or at least thought about, the role that viperin might play in protection against the novel SARS-CoV-2 coronavirus?

Jack Hsu, PhD:

We actually just set up a new experimental facility, for safety reasons, where we are beginning to look at how viperin as well as the small molecule ddhCTP impact SARS-CoV-2 viral replication in cells. We haven’t done many experiments yet, but so far we've seen a small decrease in viral replication, though we need to repeat this and need to optimize the system to make sure that it’s reproducible.

Arthur N. Brodsky, PhD:

That’s encouraging to hear, hopefully that work will bear fruit in the future. Before we wrap up, could you share a bit about how important CRI's support has been for you and the important research that you're conducting?

Jack Hsu, PhD:

CRI’s support via the postdoctoral fellowship program has been very important for me. It allows me to do research, of course, to understand how our immune system fights viral infection. It also enables me to go to scientific conferences, where I have been able to meet, learn from, and form relationships with other scientists in the CRI community and the immunology field in general. This is very important for my research because we need to keep updated, so we need to know about the new findings in the field.

Personally, my background is not in cancer research, it’s more in cell biology and immunobiology. The fellowship actually provides me excellent chances to engage the cancer research and cancer immunobiology communities.

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