Herpesviruses

Herpesviridae Basics

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

  • grow rapildly
  • lytic
  • latency in sensory ganglia usually
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Betaherpesviruses

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

  • infect/latent in lymphocytes
  • associated with oncogenesis 
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Herpesviruses and host-specificity

  • 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 
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Herpesvirus genes

  • 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 
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Herpesvirus genome

  • 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
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Herpesvirus structure

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

  • 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 
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Herpesvirus latency

  • 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 
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Herpesvirus detection and diagnosis

  • 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
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Bovine Herpesviruses

  • 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 
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BoHV1, BHV-1 Infectious Bovine Rhinotracheitis Vir

  • 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 
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Infectious Bovine Rhinotracheitis (IBR)

  • 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)
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Infectious Pustular Vulvovaginitis (IPV) or Balano

  • genital transmission
    • fever
    • vulval labia inflamed, reddened mucosa with pustules, vulvar discharge
    • frequent micturition
    • balanoposthitis (inflamed penis with pustules)
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Epidemiology and control of BoHV1, BHV-1

  • 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 
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Vaccination for BoHV1, BHV-1

  • 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
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Bovine Herpesvirus-2, BoHV2, BHV-2 bovine mammilli

  • 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
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Malignant Catarrhal Fever

  • 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)
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Bovine herpesvirus 5, BoHV5

  • 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
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Porcine Herpesviruses

  • 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 
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Suid herpesvirus 1, SuHV1, Aujeszky's Disease of p

  • 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
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Aujesky's disease (Pseudorabies) in Natural Host

  • 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 
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Pathogenesis of Aujeszky's disease

  • 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 
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Aujesky's disease (Pseudorabies) other species

  • 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?)
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Eradication of SuHV1 from UK

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 

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Vaccines for Aujeszky's disease

  • 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 
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Gallid herpesvirus 1, GaHV1, avian infectious lary

  • 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 
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Gallid herpesvirus 2, GaHV2, Marek's disease virus

  • 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 
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