Herpesviruses

• large DNA viruses
• cause multi-systemic disease
• latency
• may be oncogenic
• highly species adapted - complex pathogenesis 

• grow rapildly
• lytic
• latency in sensory ganglia usually

• grow slowly
• non-lytic
• latent in myeloid precursors

• infect/latent in lymphocytes
• associated with oncogenesis 

• usually very host-specific 
• several human viruses appear to have counterparts in domestic animals 
• sometimes cause severe disease in the 'wrong' host
  • SuHV1 - Aujeszky's disease virus - pig virus is fatal in dogs and cats (pseudorabies)
  • cercopithecin HV-1 - monkey virus is fatal in man (B-virus)
  • OvHV2 is fatal in cows (malignant catarrhal fever)
• they can sometimes be transmitted to rodents - useful for modelling 

• encode many genes that modulate host inflammatory innate and specific immune responses (often captured from host)
  • SuHV1
    •  UL49.5 protein blocks TAP (transporter associated peptide) and triggers degradation 
    • gG binds and inhibits chemokines 
    • gE-gI FcR blocks complement mediated lysis 
    • MHC-like molecules - interfere with NK cells
    • interferes with IFN pathways 

• linear dsDNA genome 
• 125-290 kbp 
• 70-100 genes 
• microRNA
• control RNAs
• two unique regions flanked by repeated elements - genome structure/position of gene blocks defines the sub-families 
• genome circularises upon entry and replication in nucleus
• genome is episomal during latency
• restriction fragment length polymorphism (RFLP) useful for epidemiology e.g BoHV1 EHV1 EHV4

• icosahedral capsid -125nm surrounded by proteinaceous tegument (matrix), then membrane envelope with several glycoproteins 
• enveloped
• virion is 200nm in diameter

• easily inactivated
• transmission by close contact especially mucosal, sexual, mother-offspring 
• sneezing/droplet spread in high density populations - longer distance if cool and moist
• rare vertical transmission - fish HHV-6 integrated into chromosomes
• resevoir in latently infected hosts 

• virus maintained in differentiated cells without replication 
• little to no viral transcription 
  • herpes simplex virus expresses LAT microRNAs in neurones
  • Epstein Barr virus expresses limited set of latency associated genes in B cells
• viral genome is episomal - extrachromosomal circle or integreated into chromosome 
• latent in neurones, lymphocytes, myeloid precursors 
• often need to detect genome to detect infection 
• peripheral replication>spread>latency>reactivation>replication> shedding>recurrence/recrudescence
• reactivation associated with stress 

• serology - ELISA or neutralising antibody - may not be ablet to distinguish between acute/latent
• histopathology - polykaryocytes, intranuclear inclusions, mononuclear cell infiltration
• immunohistochemistry eg fluorescent antibody staining (FA)
• EM on sections from lesion
• isolation of virus by appropriate tissue culture, then FA 
• detection of DNA by PCR-based methods 
  • latently infected cells can be detected using molecular probes
  • in some cases RFLP using purified virus DNA is useful for epidemiology

• Alphaherpesvirinae 
• BoHV1, BHV-1
  • infectious bovine rhinotracheitis (IBR)
  • infectious pustular vulvo-vaginitis (IPV)
• BoHV2, BHV-2
  • bovine (ulcerative) mammillitis (allerton virus) - pseudo lumpy skin disease 
• BoHV5, BHV-5 
  • bovine encephalitis virus 

• Gammaherpesvirinae
• bovine malignant catarrhal fever
  • acelaphine herpesvirus-1 (antelope family) Wildebeest herpesvirus
  • ovine herpesvirus-2
• BoHV4, BH4-4 
  • genome similar to Epstein Barr virus
  • linked to uterine microbial disease of cattle after parturition 

• alphaherpesvirinae, varicellovirus
• causes respiratory disease, abortion
• infects mucosal and neural tissues 
• replication cycle is 12-24 hrs
• gaglionic latency is important 
• high dose of corticosteroids efficiently cause reactivation 

Transmitted by 2 routes:

• Respiratory - common in recent years 
  • trigeminal ganglion becomes latently infected
  • respiratory disease but also congenital disease and abortion
• Genital - infectious pustular vulvovaginitis (IPV)/Balanoposthitis
  • sciatic ganglion becomes latently infected 
  • IPV much rarer disease but may be a common infection
  • relatively mild, endemic in Europe 

• aerosol transmission
• incubation period 2-3 days
• sub-clinical, mild or severe disease
  • coughing is often first sign
  • fever for 7-10 days - milk yield drops 
  • discharge from nose - serous then mucopurulent 
  • vesicles on the muzzle and in the nares - pustules, may ulcerate 
  • conjunctivitis common
  • enteritis
  • systemic disease of newborn calves - gastroenteritis, often fatal
  • abortion common (4-7 month gestation)
  • respiratory signs may last for several weeks - economic loss
• (shipping fever)

• genital transmission
  • fever
  • vulval labia inflamed, reddened mucosa with pustules, vulvar discharge
  • frequent micturition
  • balanoposthitis (inflamed penis with pustules)

• described in feedlot cattle in USA in early 1950s - rednose
• RFLP of genome for strain identification 
  • new strains introduced to UK via europe in late 1970s
  • 'cooper' from USA more pathogenic than 'Oxford' or 'K22' strains
• voluntary eradication scheme: accredited herds are seronegative
  • 4% of 100,000 UK herds
• eradicated from Austria, Denmark, Finland, Sweden, Switzerland, Norway by test and slaughter/removal
• europe has compulsory notification of BoHV1 status and this affects trade
• antibody positive animals not allowed into AI schemes 
• OIE list B disease 

• available but poorly effective
• attenuated - may be abortogenic
• modified live - eg double deletion gE/TK
• non-replicating, killed (intranasal)
• subunit 
• replicating vaccines appear to transmit with low efficiency
• will prevent clinical disease but not latent infection and reactivation from wild-type virus 
• germany using gE DIVA vaccination approach to control

• alphaherpesvirinae, simplexvirus 
• clinical form 1
  • lesions on teats and if severe, udder
  • may become swollen, severe oedema, vesicles, ulcers
  • ganglionic latency and reactivation
  • cases tend to be seasonal - reason unknown - other factors? (insect vector?)
  • not uncommon but not a major problem 
• clinical form 2 
  • generalised skin disease, pseudo-lumpy skin disease
  • mild, skin nodules with central depression lead to necrosis
  • need to differentiate from pox virus - lumpy skin disease in Africa and Asia
• localised spread in skin and viraemia
• may have an insect vector 
• may be a wildlife reserveoir eg buffalo, giraffe

• Alcelaphine HV1 (AlHV1) - malignant catarrhal fever virus (has been isolated) OR
• Ovine HV2 (OvHV2) - ovine-associated malignant catarrhal fever virus (DNA clone sequenced but not grown in tissue culture)

• gammaherpesvirinae, macavirus genus 
• MCF in cattle is a severe and fatal lymphoproliferative disease 
• disease also seen in wild ruminants (deer, bison, antelope) and pigs
  • fever 
  • lesions of the mucosae - respiratory and GI tracts
  • crusted, erosive lesions on the muzzle, oral cavity
  • nasal and ocular discharges and bilateral corneal opactiy (blindness)
  • neurological signs
  • lymphadenopathy
  • death  by 2 days - several weeks after clinical signs 
• In Africa/zoos AlHV1 reservoir is wildebeest that shed virus especially at calving time 
• In UK - OvHV2 reservoir is sheep that infect in-contact cattle via nasal secretion year round
• subclinical infection in wildebeest and sheep
• no transmission among cattle (dead-end host)

• bovine encephalitis virus
• alphaherpesvirus, varicellovirus
• historically thought to be caused by specific BoHV1 strains (BHV-1.3) but renamed BoHV5
• fatal meningoencephalitis of calves
• direct neural spread from nasal cavity, pharynx, tonsils via maxillary and mandibular branches of the TG 
• lesions in midbrain then entire brain
• BoHV1 vaccine may protect from BoHV5

• Alphaherpesvirinae - varicellovirus
  • SuHV1 - psuedorabies virus
• Betaherpesvirninae - unassigned genus
  • SuHV2 pig cytomegalovirus - inclusion body rhinitis 
• Gammaherpesvirinae - Macavirus
  • SuHV3, 4, 5 - pig lymphotropic herpesvirus 1, 2, 3 

• pig major host and reservoir (latency)
• very pathogenic virus (including its natural host)
  • extremely lytic, rapid replication cycle (12h)
  • highly neurotropic - can be used as a neurotracer
  • relatively wide host range (not infectious to man)
  • fatal in other species 
    • horses, cattle, sheep, goats, dogs, cats etc
• infects wide variety of cultured cells of different species
• easy to work with in laboratory and in animal models of infection
• latency in neurons and lymphoid tissue
• seropositive animals are latently infected
• eradicated from UK in early 1990s

• 0-10 days old piglets
  • unrest, duck-like posture, profuse salivation, convulsions, death
• 10-28 day old piglets 
  • agitated, circling, sneezing, neurological signs, death likely
• fatteners 
  • growth retardation, cough, sneeze, respiratory stress, dog-like posture, mortality about 5%
• sows and boars
  • mild - may be sub-clinical profuse salivation
• pregnant sows
  • often abort (5-60%) or premature parturition with abnormal litters (in endemic areas abortion may be the only sign that disease is present)
• disease severity reduced in piglets from a seropositive sow 

• virus infects the epithelial cells of the URT
• translocates via axons of sensory nerves
• infects neurons - ganglionitis (latency)
• transmitted on to CNS - encephalitis 
• also infects lymphoid tissue e.g. tonsils (latency)
• transmission by aerosol - saliva, nasal discharges 
• can get continuous shedders in nasal discharges, few mucosal lesions 

• universally fatal in 
  • dogs, cats, cattle, foxes, and minks 
  • rodents (experimentally)
• pruritis (violent) at inoculation site with self-mutilation is a dominant sign leading to convulsions, coma and death
• pseudorabies - dogs - paralysis of jaws/pharynx, drooling, howling, but not agressive 
• man appears to be resistant (zoonosis with pig heart transplants?)

Commenced 1982/83

• became notifiable
• vaccines witheld
• slaughtered all pigs on infected farms (for human consumption)
• tested sera from slaughtered pigs and investigated any +ve farms

complete by 1993 - very expensive

re-introduction of infection remains a possibilty 

• incativated, modified live - DIVA gene-deleted (TK plus gE) eg strain 783 (TK-,gE-)
• Pro -
  • ELISA for anti-gE in serum can distinguis vaccine from wt strains
• Con -
  • does not prevent latency,
  • doesnt prevent transmission following wt infection,
  • can recombine with wt strains,
  • vaccination alone does not eradicate infection from pig population

• current european strategy is to vaccinate to reduce incidence then slaughter seropositive 

• alphaherpesvirinae, iltovirus
• chickens worldwide (and pheasants) 
• mild coughing, sneezing then nasal and ocular discharge, becomes laboured breathing, rasping coughing 
• strains range in virulence - 100% morbidity, 20-70% mortality 

• alphaherpesvirinae, mardivirus
• highly cell associated
• oncogenic - CD4+ T lymphocytes are transformed
• transforming proteins/molecules
  • meq - inhibits lytic replication, activates T cell proliferation (c-jun/p53)
  • viral telomerase RNA (vTR)
• latency in CD4+ T lymphocytes 
  • integrated in telomeres
  • essential for transformation
• cell free virus in feather follicle (epithelial cells) - virus released in dander
• transmission - inhalation of dander
• originally (1930s-1950s) mild polyneurtitis - neurological signs - assymetric paralysis 
• lymphoproliferative diseases of chickens within 2-6 weeks of infection 
• visceral lymphomas
• cutaneous lymphomas
• vaccination has reduced disease but not infection - in ovo or at hatching