New Insights into Equine Herpesvirus-1 (EHV-1) Neurological Disease

This is an excerpt from Equine Disease Quarterly, funded by underwriters at Lloyd's, London, brokers, and their Kentucky agents.

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EQUINE DISEASE QUARTERLY

Outbreaks of neurological disease caused by hypervirulent strains of EHV-1 have been reported with increasing and near-alarming frequency during the past several years (see the July 2003 issue of the Equine Disease Quarterly). This disease is characterized by high morbidity and case fatality rates, resistance to prevention by vaccination, and the ability to affect horses of all breeds, ages, and vaccination status. EHV-1 neurological disease has the potential for causing catastrophic losses to both the welfare of horses and the economy of equine-based businesses.

A major milestone in our understanding of the neurological form of EHV-1 infection recently has been achieved following a five-year, internationally collaborative research effort by scientists at the Maxwell H. Gluck Equine Research Center in the United States and the Animal Health Trust in the United Kingdom. With an eye toward identifying a genetic basis for the neuropathogenic phenotype of EHV-1, the DNA sequence of several key genes of the herpesvirus was determined for virus isolates collected from 48 outbreaks of EHV-1 neurological disease and 82 outbreaks of EHV-1 abortion without accompanying neurological involvement. The disease outbreaks occurred over a 35-year time span in eight different countries. An unanticipated outcome of the comparative genomics study was the finding of a single point mutation uniquely present in EHV-1 isolates from 83% of the neurological disease outbreaks and uniquely absent from 95% of EHV-1 abortion outbreaks. Importantly, the identified mutation that is highly associated (p<0.0001) with the capacity of an EHV-1 strain for causing neurologic signs in the horse is located in the catalytic subunit of the gene encoding the viral DNA polymerase. This discovery of a mutation-associated, monogenic determinant of EHV-1 neuropathogenicity has given rise to the hypothesis that underlying the pathogenetic basis of a neurologic EHV-1 strain is the acquired viral attribute of enhanced replicative aggressiveness made possible by a single, mutation-induced alteration of the enzymatic properties of its replicative polymerase. Recent empirical support of the hypothesis was provided by studies, supported by the Grayson-Jockey Club Research Foundation, Inc., demonstrating a fivefold greater level of virus delivered by viremic leukocytes to the blood vascular endothelium of the central nervous system of horses infected by paralytic strains of EHV-1 (Figure 1).

Two practical benefits have resulted from this first genetic characterization of neuropathogenic strains of EHV-1 and the ensuing discovery of a disease-conferring mutation that can be used as a genetic marker for identifying and tracking such mutant strains of the virus. First, the Maxwell H. Gluck Equine Research Center at the University of Kentucky, in partnership with the University's Livestock Disease Diagnostic Center (LDDC), is providing real-time surveillance of the prevalence and distribution of neuropathotype strains of EHV-1 as latent viral DNA in Kentucky's large Thoroughbred population. Submandibular lymph nodes collected from horses submitted to the LDDC for postmortem examination are being tested for the presence of latent neuropathotype strains of EHV-1 by polymerase chain reaction and subsequent DNA sequencing of the amplified polymorphic region of the latent EHV-1 DNA. The collaborative effort is part of the LDDC’s new epidemiology initiative designed to monitor disease trends and to identify and track emerging infectious disease threats to Kentucky’s livestock-based economy (see the October 2005 issue of the Equine Disease Quarterly). Second, a molecular diagnostic technique has been developed for antemortem detection of mutant EHV-1 DNA present in tissue biopsies from the submandibular lymph nodes of latently infected carrier horses. These lymph nodes may act as reservoirs for the potential spread of neuropathotype strains of EHV-1. The neuropathotype carrier-identification procedure provides the option of an additional, test-and-segregate approach for minimizing the risk of outbreaks of EHV-1 neurological disease resulting from latent virus reactivation in carrier horses.

Despite the success of current-generation vaccines in reducing the losses from EHV-1 abortigenic disease over the past 25 years, the mutant neuropathotype EHV-1 strains have acquired an enhanced replicative vigor that allows them to overcome the level of immune responses induced by such vaccines. Two questions remain: what selective pressures favor the emergence and continued maintenance of such virus mutants and whether a causal connection exists between vaccine refractoriness of the neuropathotype EHV-1 strains and the apparent recent upsurge in their occurrences. However, the unsettling proposition of an emerging hypervirulence of EHV-1 and its evolving toward neuropathogenicity presents a daunting challenge to both equine researchers and vaccine manufacturers: development of new-generation vaccines with an increased protective efficacy commensurate with the evolved increase in virus virulence.

CONTACT:
Dr. George Allen, 859/257-4757, gallen@uky.edu
Maxwell H. Gluck Equine Research Center, University of Kentucky, Lexington, Ky.

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Equine Disease Quarterly

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