54       Herpesviridae

 

The family Herpesviridae contains more than 100 viruses. Fish, amphibians, reptiles, birds and mammals including humans are susceptible to herpesvirus infection. These viruses are of special importance because of their widespread occurrence, their evolutionary diversity and their involvement in many important diseases of domestic animals and humans. The name, herpesvirus (Greek herpein, to creep), refers to the sequential appearance and local extension of lesions in human infection. Herpesviruses are enveloped and range from 200 to 250 nm in diameter. They contain double-stranded DNA within an icosahedral capsid. Herpesviruses enter cells by fusing with the plasma membrane. Replication occurs in the cell nucleus. The envelope is probably derived from the nuclear membrane of the host cell, incorporating at least 10 viral-encoded glycoproteins. Release from the cell is by exocytosis. Active infection results in cell death. Intranuclear inclusions are characteristic of herpesvirus infections. Extension of viral infection occurs through points of cell contact without exposure of virus to neutralizing antibodies in blood or interstitial fluids. Protective antibody responses are usually directed against the envelope glycoproteins. Herpesvirus virions, which are fragile and sensitive to detergents and lipid solvents, are unstable in the environment.

The family is divided into three subfamilies comprising 13 genera. Alphaherpesviruses replicate and spread rapidly, destroying host cells and often establishing latent infections in sensory ganglia. Betaherpesviruses, which replicate and spread slowly, cause infected cells to enlarge, hence their common name, cytomegaloviruses. They may become latent in cells of the monocyte series. Gammaherpesviruses, which infect lymphocytes, can produce latent infections in these cells. When lymphocytes become infected, there is minimal expression of viral antigen. Some gammaherpesvirus species also replicate in epithelial and fibroblastic cells, causing cytolysis. A number of herpesviruses are implicated in neoplastic transformation of lymphocytes.

Clinical infections

Herpesviruses establish lifelong infections with periodic reactivation resulting in bouts of clinical disease. Shedding of virus may be periodic or continuous. During latency, the episomal viral genome becomes circular and gene expression is limited. Reactivation of infection is associated with various stress factors including transportation, adverse weather conditions, overcrowding and intercurrent infection. Natural infections with particular herpesviruses are usually restricted to defined host species. Because these viruses are highly adapted to their natural hosts, infections may be inapparent or mild. However, in very young or immunosuppressed animals, infection can be life-threatening.

Herpesviruses can cause respiratory, genital, mammary and CNS diseases in cattle (Table 54.1). Aujeszky's disease, which affects pigs and other domestic species, is the major porcine herpesvirus infection (Table 54.2). Equine herpesvirus infections are presented in Table 54.3; those of domestic carnivores are listed in Table 54.4 and those of birds in Table 54.5.

Table 54.1 Herpesvirus infections of ruminants.

Virus	Genus	Comments
Bovine herpesvirus 1	Varicellovirus	Causes respiratory (infectious bovine rhinotracheitis) and genital (infectious pustular vulvovaginitis, balanoposthitis) infections. Occurs worldwide
Bovine herpesvirus 2	Simplexvirus	Causes ulcerative mammillitis in temperate regions and pseudo-lumpy-skin disease in tropical and subtropical regions
Bovine herpesvirus 5	Varicellovirus	Causes encephalitis in calves; described in several countries
Ovine herpesvirus 2	Macavirus	Causes subclinical infection in sheep and goats worldwide. Causes malignant catarrhal fever in cattle and in some wild ruminants
Alcelaphine herpesvirus 1	Macavirus	Causes subclinical infection in wildebeest in Africa and in zoos. Causes malignant catarrhal fever in cattle, deer and in other susceptible ruminants

Table 54.2 Herpesvirus infections of pigs.

Virus	Genus	Comments
Porcine herpesvirus 1 (Aujeszky's disease virus)	Varicellovirus	Causes Aujeszky's disease in pigs. Encephalitis, pneumonia and abortion are features of the disease. In many species other than pigs, pseudorabies manifests as a neurological disease with marked pruritis. Occurs worldwide but USA (occurs in feral pigs), Canada, New Zeland and several EU states have eradicated this disease
Porcine herpesvirus 2	Unassigned	Causes disease of the upper respiratory tract in young pigs (inclusion body rhinitis)

Table 54.3 Herpesvirus infections of horses.

Virus	Genus	Comments
Equine herpesvirus 1	Varicellovirus	Causes abortion, respiratory disease, neonatal infection and neurological disease. Occurs worldwide
Equine herpesvirus 3	Varicellovirus	Causes mild venereal infection (equine coital exanthema) in both mares and stallions
Equine herpesvirus 4	Varicellovirus	Causes rhinopneumonitis in young horses. Occurs worldwide

Table 54.4 Herpesvirus infections of domestic carnivores.

Virus	Genus	Comments
Canine herpesvirus 1	Varicellovirus	Causes a fatal generalized infection in neonatal pups
Feline herpesvirus 1	Varicellovirus	Causes feline viral rhinotracheitis in young cats

Table 54.5 Herpesvirus infections of birds.

Virus	Genus	Comments
Gallid herpesvirus 1	Iltovirus	Causes infectious laryngotracheitis. Present in many countries
Gallid herpesvirus 2 (Marek's disease virus)	Mardivirus	Causes Marek's disease, a lymphoproliferative condition in 12- to 24-week-old chickens. Occurs worldwide
Anatid herpesvirus 1	Mardivirus	Causes acute disease in ducks (duck plague), geese and swans characterized by oculonasal discharge, diarrhoea and high mortality. Occurs worldwide

Infectious bovine rhinotracheitis and pustular vulvovaginitis

Infection with bovine herpesvirus 1 (BoHV-1) is an important cause of losses in cattle worldwide. It is associated with several clinical conditions including infectious bovine rhinotracheitis (IBR), infectious pustular vulvovaginitis (IPV), balanoposthitis, conjunctivitis and generalized disease in newborn calves. Isolates of BoHV-1 can be divided into subtypes 1.1 (IBR-like) and 1.2 (IPV-like) using restriction endonuclease analysis of the genome.

The virus is usually acquired through aerosols (subtype 1.1) or genital secretions (subtypes 1.2a and 1.2b). Aerosol transmission is most efficient over short distances and is facilitated by the close proximity of animals. Replication occurs in the mucous membranes of the upper respiratory tract and large amounts of virus are shed in nasal secretions. Virus also enters local nerve cell endings and is transported intra-axonally to the trigeminal ganglion, where it remains latent. In most instances, infection is contained within two weeks by a strong immune response. However, tissue necrosis may facilitate secondary bacterial infection, with severe systemic effects and, possibly, death. Rarely, viraemia in pregnant cows may produce foetal infection and abortion. Following genital infection, virus replicates in the mucosa of the vagina or prepuce, and latent infection may become established in the sacral ganglia. Focal necrotic lesions on genital mucosae may eventually coalesce, forming large ulcers.

In outbreaks of disease, either the respiratory or the genital form usually predominates. Swabs collected from the nares and genitalia of several affected animals during the early acute phase of the disease are suitable for virus isolation, viral DNA detection or the preparation of smears for the rapid demonstration of viral antigen using immunofluorescence. Inactivated, subunit, modified live and marker vaccines are available for control. Vaccination reduces the severity of clinical signs but may not prevent infection or alter the carrier state.

Aujeszky's disease

This disease is caused by porcine herpesvirus 1, also referred to as Aujeszky's disease virus (ADV). The pig is the natural host of the virus and infection is endemic in the pig population in many countries. The virus is shed in oronasal secretions, milk and semen. Transmission usually occurs by nose-to-nose contact or by aerosols. Following infection, the virus replicates in the epithelium of the nasopharynx and tonsils. Virus spreads to regional lymph nodes and to the CNS along axons of the cranial nerves. Virulent strains produce a brief viraemia and become widely distributed around the body, particularly in the respiratory tract. Transplacental transfer results in generalized infection of foetuses. Latency occurs in a high percentage of infected animals, with virus localized in the trigeminal ganglia and tonsils.

The age and susceptibility of infected pigs and the virulence of the infecting strain influence the severity of the clinical signs. Young pigs are most severely affected; mortality may approach 100% in suckling piglets. Neurological signs predominate in young pigs. Mortality is much lower in weaned pigs, although neurological and respiratory signs are often present. Infection in sows may result in resorption of foetuses, abortion or stillbirths. In herds with endemic ADV infection, neonatal animals are protected by maternally-derived antibody.

Specimens of brain, spleen and lung from acutely affected animals are suitable for virus isolation and viral nucleic acid detection, while cryostat sections of tonsil or brain are suitable for detection of viral antigen by immunofluorescence. If used strategically, vaccination can prevent the development of clinical disease. Modified live, inactivated and gene-deleted marker vaccines are available.

Disease in other domestic animals occurs sporadically and is characterized by neurological signs resembling those of rabies, hence the name pseudorabies. Marked pruritis is a feature of the disease. The clinical course is short, with most affected animals dying within a few days.

Equine rhinopneumonitis and equine herpesvirus abortion

Infection with equine herpesvirus 1 (EHV-1) is associated with respiratory disease, abortion, fatal generalized disease in neonatal foals and encephalomyelitis. Close contact facilitates transmission of these fragile viruses. Transmission usually occurs by the respiratory route following contact with infected nasal secretions, aborted foetuses, placentae or uterine fluids. The viruses replicate initially in the upper respiratory tract and regional lymph nodes with spread, in some cases, to the lower respiratory tract and lungs.

Abortion caused by EHV-1 occurs several weeks or months after exposure, usually during the last four months of gestation. Equine herpesvirus 1 has a predilection for vascular endothelium. Vasculitis and thrombosis in the placenta, along with transplacental infection of the foetus, results in abortion. Infected mares rarely abort during subsequent pregnancies and their fertility is unaffected. Infection close to term may result in the birth of an infected foal which usually dies due to interstitial pneumonia and viral damage in other tissues, sometimes complicated by secondary bacterial infection. Vasculitis and thrombosis in EHV-1 infection may affect the CNS, especially the spinal cord. Neurological changes appear to be related to infection with particular strains of EHV-1. Although neurological signs associated with EHV-1 infection are relatively uncommon, they may present in several horses during an outbreak of abortion or respiratory disease on a farm. The signs range from slight incoordination to paralysis, recumbency and death.

Respiratory disease caused by equine herpesvirus 4 (EHV-4) occurs in foals over two months of age, in weanlings and in yearlings. Following an incubation period of two to ten days, there are signs of fever, pharyngitis and serous nasal discharge. Secondary bacterial infection is common, giving rise to mucopurulent nasal discharge, coughing and, in some cases, bronchopneumonia. Outbreaks of respiratory disease caused by EHV-1 are clinically indistinguishable from respiratory infections caused by EHV-4 but occur less frequently.

Virus isolation and viral nucleic acid detection are used routinely for the laboratory confirmation of herpesvirus infection in horses. Viral antigen may be demonstrated in cryostat sections of lung, liver and spleen from aborted foetuses using immunofluorescence.

Effective management practices and vaccination are essential for control. Animals returning from sales, races or other events should be segregated for up to four weeks. On large stud farms, horses should be kept in small, physically separated groups. Modified live and inactivated virus vaccines are commercially available. As vaccination is not considered to be fully protective, frequent boosters are recommended. Vaccination appears to reduce the severity of clinical signs and to decrease the likelihood of abortion.

Canine herpesvirus infection

Infection in domestic and wild Canidae caused by canine herpesvirus 1 (CHV-1) is common worldwide. Clinical disease occurs in neonatal pups and is characterized by generalized infection and high mortality.

Infection usually occurs by the oronasal route following direct contact between infected and susceptible animals. During periods of stress, latent infections may be reactivated, with shedding of virus. The sites of latency include sensory ganglia. Virus is shed in oronasal and vaginal secretions. Newborn pups, which can acquire infection either during parturition or in utero, may transmit infection to littermates.

Following infection, CHV-1 replicates in the nasal mucosa, pharynx and tonsils. The virus replicates most effectively at temperatures below normal adult body temperature. Because the hypothalamic regulatory centre is not fully operational in pups under four weeks of age, they are particularly dependent on ambient temperature and maternal contact for maintenance of normal body temperature. A cell-associated viraemia and widespread viral replication in visceral organs can occur in infected neonatal animals with subnormal body temperatures. Affected pups stop sucking, show signs of abdominal pain, whine incessantly and die within days. Morbidity and mortality rates in affected litters are high. Bitches whose pups are affected tend to produce healthy litters subsequently.

Diagnostically significant postmortem findings include focal areas of necrosis and haemorrhage, particularly in the kidneys. Intranuclear inclusions are usually present. Specimens from liver, kidney, lung and spleen are suitable for virus isolation or detection of viral nucleic acid. A commercial vaccine is available. Affected bitches and their litters should be isolated to prevent infection of other whelping bitches.

Feline viral rhinotracheitis

This acute upper respiratory tract infection of young cats is caused by feline herpesvirus 1 (FHV-1). The virus, which occurs worldwide, accounts for about 40% of respiratory infections in cats.

Close contact is required for transmission. Most recovered cats are latently infected. Reactivation with virus replication and shedding is particularly associated with periods of stress such as parturition, lactation or change of housing. Initially, FHV-1 replicates in oronasal or conjunctival tissues before infecting the epithelium of the upper respiratory tract. Secondary bacterial infections, which commonly occur, exacerbate the clinical signs. Young cats display signs of acute upper respiratory tract infection including fever, sneezing, inappetence, hypersalivation, conjunctivitis and oculonasal discharge. In more severe disease, pneumonia or ulcerative keratitis may be evident. The mortality rate is low except in young or immunosuppressed animals.

Clinical differentiation of feline viral rhinotracheitis from feline calicivirus infection is difficult. Virus can be isolated from suitable tissue specimens or viral DNA can be detected in oropharyngeal or conjunctival swabs. Specific viral antigen can be demonstrated in acetone-fixed nasal and conjunctival smears using immunofluorescence. Good husbandry practices and disease control procedures should be implemented in catteries together with regular vaccination to minimize the impact of clinical disease. Commercial vaccines also contain feline calicivirus. The protection provided by vaccination against these two viruses is incomplete as vaccinated cats can become infected but clinical signs tend to be much reduced.

Marek's disease

This contagious lymphoproliferative disease of chickens is caused by gallid herpesvirus 2 (Marek's disease virus), which is cell-associated and oncogenic. The disease, which is of major economic significance in the poultry industry, occurs worldwide. Productive replication with release of infective virus occurs only in the epithelium of the feather follicle. Cell-free virus is released from the follicles along with desquamated cells. This dander can remain infective for several months in dust and litter in poultry houses. Infected birds remain carriers for life and their chicks, which are protected initially by maternally-derived antibody, acquire infection within a few weeks, usually by the respiratory route. In addition to the virulence of the infecting strain of herpesvirus, host factors which contribute to the severity of the disease include the sex, age at the time of infection and genotype. Female birds are more susceptible than male birds, while resistance to the development of disease increases with age. The bird's genotype influences the susceptibility of T lymphocytes to transformation and development of lymphoid tumours. Birds between 12 and 24 weeks of age are most commonly affected when clinically affected birds present with partial or complete paralysis of the legs and wings.

The diagnosis of Marek's disease is based on clinical signs and pathological findings. Differentiation from lymphoid leukosis is based on the age of affected birds, the incidence of clinical cases and the histopathological findings. The use of appropriate management strategies, genetically resistant stock and vaccination have reduced losses from Marek's disease. Disinfection, all-in/all-out policies, and rearing young chicks away from older birds for the first two or three months of life reduce exposure to infection, decreasing the likelihood of serious disease. A range of modified live vaccines are commercially available. Although a single dose of virus injected into day-old chicks provides good lifelong protection, it does not prevent superinfection with virulent field viruses. Automated in ovo vaccination is used in large commercial units.