Switching ‘off’ equine herpesvirus

One of the most common EHV species is EHV-1, a highly infectious virus that can cause serious illness including respiratory disease, neurological disease, abortions and neonatal death. Current vaccines don’t prevent EHV-1 infection and available therapies only offer supportive care.

Conn is an assistant professor at the Western College of Veterinary Medicine (WCVM) who specializes in virology and virus-cell interactions. While her previous research focused on herpes simplex virus (HSV) in humans, Conn now studies herpesviruses that infect cattle and horses in addition to her HSV research. Her initial EHV research, which was supported by the Townsend Equine Health Research Fund (TEHRF) in 2019, investigated how EHV-1 protein expression is regulated — vital information for further research.

With funding from MAF, Conn will explore how the EHV-1 virus takes over host cells by harnessing their biological processes to make more virus particles (virions). Conn will then explore how these basic interactions can be targeted — helping the cells “switch off” the invading virus and stop replication. Findings may eventually play a role in the development of new antiviral therapies.

Read the Q & A to learn more about Conn’s EHV research work.

Q. When did you begin studying equine herpesvirus (EHV)?

Before coming to the WCVM, my research was purely focused on herpes simplex virus (HSV). I started the equine herpesvirus project when I came here and funding from the TEHRF award  supported this new research avenue. TEHRF funding supported the preliminary data that I included in my successful Morris Animal Foundation (MAF) proposal.

Q. What can a scientist whose previous work focused on HSV in humans contribute to EHV research?

I think I'm just building on the expertise that I’ve gained from working in the HSV field. I was the first researcher to look at histone dynamics during HSV infection and that led to the discovery that ICP4 (the major regulatory protein of HSV) dysregulates histone chromatin interactions, which may represent a new transcription regulatory mechanism for a viral protein. The expertise and groundwork that I started in the HSV field transfers well into the EHV field. Plus, I think molecular studies of EHV replication is a growing field — it's a nice niche that I can fit into.

Q. What have you learned so far about EHV? What’s your next step?

I first evaluated how EHV infection affects the nuclear mobility of cellular histones (basic proteins that help condense DNA into chromatin, which is the structure that controls DNA replication and gene expression). We found that like herpes simplex virus, EHV infection disrupts chromatin. Histone proteins are more mobile, which means that their binding and unbinding to chromatin is dysregulated during infection.

Our next step is to evaluate the viral chromatin more directly to see if the unstable structure of the HSV chromatin is conserved. We will also look at whether IE1 (the major transcription activator in EHV) directly or indirectly regulates histone chromatin exchange. In HSV, the equivalent major transcription activator is called ICP4. Both IE1 and ICP4 are essential for producing progeny virions (infectious virus particles), and they’re both essential for activating viral gene expression. They’re the “switch” that turns on viral protein expression, which is necessary to make progeny virions.

Q. Why is it helpful to study both EHV and HSV?

Viruses are like intracellular parasites — they need to use the cell machinery to make the viral proteins and replicate the viral genomes to make more virus. HSV and EHV are closely related, so we're seeing how they're similar and different and learning how these characteristics might cross over between horses and humans.

For both HSV and EHV, we’re looking at how viral proteins regulate expression of the viral genes. One difference between the two viruses is that EHV has an extra transcription regulator called IR2 that inhibits IE1 functions and basically shuts down transcription. If we can figure out how both IE1 and IR2 work, then that will help inform how we might design a new antiviral therapy that targets virus replication and prevents progeny virus production.

Q. Why is it so important to understand the basic functions of EHV-1?

In cases where you do have an EHV outbreak and disease development, current antiviral therapies don't directly target the virus. My understanding is that veterinarians can only treat the symptoms and hope the horse pulls through.

From my side of things, to make more virus you need to express viral proteins. And we know that IE1 is critical for producing progeny virions. If we better understand how IE1 works, we may be better able to target those activities with a new antiviral therapy. We could target the virus directly and prevent new virus production, which would prevent disease progression and spread. But to target it, you need to know how it works.

Click here to read more background about Conn’s EHV research work.