Equine herpesvirus types 2 and 5 (EHV-2 and EHV-5), unlike other equine herpesviruses, continue to baffle researchers regarding their roles in disease and reactions to antiviral drugs, said one infectious disease expert.

EHV-2 and –5 are gamma-herpesviruses, as opposed to alpha-herpesviruses like EHV-1 and –4. Their “strategy” could be to evade horses’ immune systems without making the animals very sick—meaning they might thrive as “innocent bystanders,” said Lutz Goehring, DVM, MS, PhD, Dipl. ACVIM, Warren Wright Sr., Lucille Wright Markey Endowed Chair in Equine Infectious Diseases at the University of Kentucky’s Gluck Equine Research Center, in Lexington.

“These are viruses that are well-versed around horses, and they know the horse very well; they know its immune system very well, and they know how to evade that immune system very well,” Goehring said during the 2021 American Association of Equine Practitioners convention, held Dec. 4-8  in Nashville, Tennessee.

“Their infections are typically characterized by mild disease or nonclinical cases, with few exceptions, because that’s the strategy of the virus,” he said. “These viruses do not want to kill their host.”

It’s apparent alpha-herpesviruses EHV-1 and EHV-4 can cause serious disease with respiratory or neurologic signs, he said. But the effects of the gamma herpesviruses—EHV-2 and EHV-5, as well as asinine herpesviruses 2, 4, and 5 (AHV-2, AHV-4, and AHV-5), more commonly seen in donkeys—remain unclear.

EHV-2 and -5: Most Everyone’s Had It

With the gamma-herpesviruses the first exposure and initial infection can occur as early as in the first 10 days of a foal’s life, likely acquired from the dam, but unlikely to be acquired in utero, he said. This first-time infection is more commonly associated with fever and mild upper respiratory disease in the foals, said Goehring.

In adult horses EHV-5 appears to be related to a rare disease called equine multinodular pulmonary fibrosis (EMPF), because the nodules in the lung are filled with EHV-5 genetic material, he said.

Beyond these two scenarios, pathologies related to the equine gamma-herpesviruses remain debatable, Goehring said. “We’re still always hovering at that (question), is it causing disease or not?”

Scientists suspect equine gamma-herpesviruses have accompanied equids through evolution longer than alpha-herpesviruses. One clue pointing to this theory is that they are endemic in Iceland, an island nation that has been closed to equine imports for more than 100 years. By contrast, Iceland has always been EHV-1-free, he said. The country does have EHV-4, but scientists suspect that type is slightly older than EHV-1.

Most of the world’s horses have acquired—and overcome—EHV-2 and EHV-5 infections and maintain the virus in a subset of immune cells in, usually, a latent state, he said. They are readily found in samples taken throughout the body. “(It’s like) whenever you lift a rock and look underneath, there’s a gamma-herpesvirus coming out,” Goehring said.

“If certain immune cells become involved in a disease, there is a big chance that we will also find the DNA of gamma-herpesviruses,” Goehring told The Horse after his presentation. “So virus can be an innocent bystander, follower, or beneficiary of the condition.”

Scientists don’t know what triggers the virus to enter an active state that includes replication and shedding, although some studies suggest stress—such as travel—could be a factor. Numerous studies aiming to make associations between gamma-herpesviruses and health, reproductive, or performance problems (other than the studies mentioned above) have been inconclusive, said Goehring.

Valacyclovir Unlikely to Help

Goehring also cast doubt on the efficacy of valacyclovir, the antiviral commonly used to control EHV-1 and EHV-4 outbreaks. Valacyclovir gets transformed into its useful form, acyclovir, in the horse’s liver and then is distributed into the virus-containing cells. The idea is to disrupt protein formation in the virus’ genetic makeup so the two copies of the double helix don’t match up, making the virus fail. But to be effective, acyclovir must be able to stay inside the cell with the virus, which requires a small but important transformation in the drug once it’s inside the cell. Interestingly, said Goehring, the virus itself provides the enzyme that causes this transformation—called phosphorylation—of the drug molecule to keep it inside the cell.

That’s where the problems might lie, he said. Alpha-herpesviruses appear to have a replication cycle that promotes more regular production of that needed enzyme. But gamma-herpesviruses have a far slower replication cycle, and so they contribute to acyclovir’s modification far less frequently. For this reason, the drug often can’t stay in the cell and work its effect on the virus, and so treatment is less effective.

In practice, clinicians should rethink the use of valacyclovir as a treatment if they suspect EHV-2 or EHV-5 is responsible for a horse’s disease and focus instead on controlling inflammation and modulating the immune response, Goehring said.

Looking Toward the Future

Going forward, research should focus on how equine gamma-herpesviruses replicate, namely the activities of their transcriptome and proteomes, said Goehring. Scientists also need to find solid, reliable research models for better understanding and testing the roles of these viruses—if any—in various health, breeding, and performance issues.