Feline gamma herpesvirus in Cats (Felis) | Vetlexicon
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Feline gamma herpesvirus

ISSN 2398-2950


Synonym(s): Felis catus gammaherpesvirus 1 (FcaGHV1), (Bovine herpesvirus-4 is another gammaherpesvirus which can infect cats)

Introduction

Classification

Taxonomy

  • Order: Herpesvirales 
  • Family: Herpesviridae 
  • Subfamilies: Gammaherpesvirinae and Alphaherpesvirinae 
  • Genus: Varicellovirus 

Distribution

  • Felis catus gammaherpesvirus 1 (FcaGHV1):
    • Worldwide. 
  • Bovine herpesvirus-4 (BHV-4):  
    • Worldwide in cattle. 
    • Has been detected in domestic cats in Michigan but not California, USA. 
  • Gammaherpesviruses have also been identified in the bobcat (Lynx rufus), puma (Puma concolor), the endangered Tsushima leopard cat (Prionailurus bengalensis euptilurus) and Canadian lynx (Lynx canadensis). 

Significance

Felis catus gammaherpesvirus 1 (FcaGHV1) 

  • Felis catus gammaherpesvirus 1 (FcaGHV1) was first reported in domestic cats in 2014. 
  • Investigation is ongoing into whether FcaGHV1 could cause lymphoma of FIV-infected cats, since human herpes viruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), are causal in 30-95% of HIV-associated lymphomas in humans. However, no association between FcaGHV1 and feline lymphoma was found in 122 and 17 cases. 
  • Further investigation is required to establish if FcaGHV1 could be a cause of hypertrophic cardiomyopathy: the majority of FcaGHV1 positive cats admitted to a Swiss clinic were presented for cardio-respiratory signs, rather than lymphoma, and three of the seven had hypertrophic cardiomyopathy (Novacco et al, 2019). FcaGHV1 DNA has been found in heart tissue (Beatty et al, 2014).  
  • However, while the virus is common, it is expected that it would rarely cause disease.

Bovine herpesvirus 4 (BHV4)   

  • A herpesvirus erroneously called FHV-2 was apparently isolated from a cat with feline lower urinary tract disease (FLUTD Feline lower urinary tract disease (FLUTD) ) but later identified as a bovine herpesvirus (Kruger et al, 1989). It was later postulated that what had occurred was laboratory contamination of cell culture with Bovine herpesvirus-4 due to failure to filter fetal bovine calf serum which is used to grow cell culture (Chiu et al, 2000; Thiry et al, 1991, citing Kit et al, 1986).   
  • BHV4  is a gammaherpesvirus.  
  • BHV4 antibodies were detected by an indirect immunofluorescent antibody (IFA) test in sera obtained from 31% (44/141) of cats with FLUTD and 23% (6/26) of control cats. The prevalence of positive BHV4 IFA test results in affected cats was not significantly different from that observed in control cats (Kruger et al, 1991) which appears to rule out BHV4 as an etiologic agent of FLUTD.   
  • Nevertheless, laboratory infections of cats with BHV4 does cause microscopic hematuria and focal lymphoid cystitis. 
  • No studies have been published using sensitive PCR technology specific to BHV4 to settle this question. 

Active Forms

Active Form 1

Morphology

  • Herpesviruses are enveloped.  
  • Size: 150-200 nm 
  • Large double-stranded DNA genome. 

Taxonomy

  • Order: Herpesvirales
  • Family: Herpesviridae
  • Subfamilies: Alphaherpesvirinae and Gammaherpesvirinae.  
  • Gammaherpesviruses can be further divided into four genera: LymphocryptovirusMacavirusRhadinovirus, and Percavirus
  • FcaGHV1 is a Percavirus and closely related to the gammaherpesviruses of lynx and bobcat.  
  • BHV4 is a Rhadinovirus

Tolerances

  • This section is derived from general knowledge of herpes viruses, since no specific information available for feline gammaherpesviruses. 
Temperature
  • Unlikely to be tolerant of heat (because of lipoprotein envelope). 
Humidity
  • Herpes viruses are fragile, surviving in a damp environment for only 18 h and a dry environment for 12 h. 
Other
  • Susceptible to most disinfectants: bleach diluted 1:32 in water with washing-up liquid is recommended, but any disinfectant with detergent activity would be effective. 
  • When choosing a disinfectant, bear in mind that deficiency of the enzyme UDP-glucuronosyl transferase renders the cat susceptible to the toxic effects of phenol-based disinfectants (including many essential oils). (Addie et al, 2015.) 
  • Susceptible to acid pH. 

Development

Replication
  • Gammaherpesvirus (GHV) infection is typically characterized by a brief acute replication phase followed by an extended period of viral latency in which the viral genome persists within cells with little or no viral gene expression. 
  • Virus attaches via glycoproteins to specific cell receptors. 
  • Capsid penetrates into infected cell, releasing viral DNA. 
  • Viral genes are expressed and transcribed. 
  • Viral proteins synthesized and viral particles assembled. 
  • Virus obtains envelope as it leaves cell, inducing cytolysis. 
  • Herpes viruses alternate between lytic and latent replication cycles.  
  • During viral latency, the genome is maintained as an episome and a limited repertoire of genes is transcribed. 
  • Latency-associated genes promote cell transformation and gammaherpesvirus-associated cancers, including lymphoma. 
Longevity  
  • This section is derived from general knowledge of herpesviruses, since no specific information available for feline gammaherpesviruses. 
  • Virus is fragile, surviving in a damp environment for only 18 h and a dry environment for 12 h. 
  • Survives in cell culture medium:  
    • 3 h at 37°C. 
    • Less than one month at 25°C. 
    • Several months at 4°C. 
    • Several years at -80 °C. 
Latency Gammaherpesviruses 
  • Gamma herpesviruses typically establish latent infection in a small number of lymphocytes, often within a particular lymphocyte subset, resulting in low levels of viral DNA present in the blood. 
  • Gammaherpesvirus reactivation is suspected during co-infections, or when cell-mediated immunity is compromised (Novacco et al, 2019). 
  • Cats which have been treated with glucocorticoids are more likely to be positive for viral DNA than cats who have not received glucocorticoids (Novacco et al, 2019). 

Resting Forms

Clinical Effects

Epidemiology

Transmission of FcaGHV1 

  • Since herpes viruses are fragile, indirect transmission is probably not a major source of infection other than in densely crowded situations. 
  • High virus loads found in the intestine. 
  • Horizontal transmission likely. 
  • Samples positive for DNA from any of three hemoplasma species had 19 times greater odds for testing positive for FcaGHV1 than hemoplasma negative cats, suggesting possible co-transmission (McLuckie et al, 2016; Novacco et al, 2019). 
  • Prevalence is similar to that of FIV Feline immunodeficiency virus, ie higher in older male cats. 

Transmission of Bovine Herpesvirus 

  • Route of transmission unknown, but laboratory infected cats shed virus in their urine for at least 90 days (Kruger et al, 1990). 
  • More prevalent in males than females raising possibility that it may be transmitted by biting. 
  • In one study 38% of seropositive cats were viremic, therefore iatrogenic transmission by blood transfusion is a possible risk. 
  • Seroprevalence and viremia were higher in impounded cats in one study compared with free-roaming cats, raising possibility that, as in cows, short distance aerosol transmission in catteries may be possible. 

Pathological effects

Pathological effects of FcaGHV1 

  • FcaGHV1 infection is common, but rarely causes disease. 
  • FcaGHV1 PCR-positive cats are 2.8 times more likely to be ill than healthy, but it is unknown whether FcaGHV1 is the cause of the illness, or whether the illness had reactivated latent herpes virus. 
  • In a Swiss study, five of seven FcaGHV1-positive cats had cardiorespiratory signs and three of those cats had hypertrophic cardiomyopathy. 
  • FcaGHV1 DNA can be detected in multiple tissues from infected cats, including heart tissue (but more frequently found in intestine with higher viral loads). 
  • Oncogenesis occurs in a minority of gammaherpesvirus infections, often many years after the primary infection.  
  • Predisposing factors, such as immunodeficiency, are thought to be required for lymphoma to develop.   
  • However, two studies found no evidence of FcaGHV1 infection in 122 and 17 lymphoma cases. 
  • Antibodies can be found in FcaGHV1-infected cats; therefore an antibody titer does not equate with immunity but rather is likely an indicator of latent infection. 

Pathological effects of BHV4 

  • Laboratory infections of bovine herpesvirus 4 (BHV4) infections in conventionally reared or specific-pathogen-free cats resulted in microscopic hematuria, and mild focal lymphoid cystitis (Kruger et al, 1990).   
  • BHV4-neutralizing antibodies were not detected in any serum sample obtained from cats with feline lower urinary tract disease (FLUTD) or from control cats. In contrast, BHV-4 antibodies were detected by an indirect immunofluorescent antibody (IFA) test in sera obtained from 31% (44/141) of cats with FLUTD and 23% (6/26) of control cats. The prevalence of positive BHV-4 IFA test results in affected cats was not significantly different from that observed in control cats (Kruger et al, 1991). 
  • However, there have been no reports of BHV4 detection in cases of FLUTD since the 1990s, although a recent study detected feline herpesvirus DNA in one urine sample from 102 cats with FLUTD (Lund et al, 2012): those authors did not test for BHV-4 in the urine samples. 

Control

  • Since there is nothing published about the control of FcaGHV-1 or BHV-4, the following is extrapolated from what is known of these viruses and of herpes viruses in general. 

Control via chemotherapies

  • Feline interferon omega (Virbagen Omega) Interferon has broad-spectrum anti-viral activity and may be useful in FcaGHV-1 or BHV-4 infection. 
  • L-lysine (used in human herpesvirus infection to antagonize arginine, which is necessary for formation of the herpesvirus capsid protein) is contraindicated in the cat because arginine is an essential amino acid in the cat, and reduction of plasma arginine is detrimental to immune function and severe deficiency can induce hepatic encephalopathy or even death (Morris & Rogers, 1978). 
  • Famciclovir is a guanosine analogue anti-viral which is the drug of choice for feline herpesvirus-1 infection: whether it would be a useful adjunct in treating hypertrophic cardiomyopathy or FcaGHV1-positive lymphoma (along with conventional lymphoma chemotherapy) has not been tested. 
Acyclovir Acyclovir, used for herpes simplex in man, is not recommended: it is toxic to cats if given systemically. 

Control via environment

  • Aggressive interactions and vector-borne transmission are suspected so tick and flea control may reduce FcaGHV1 transmission. 
  • Disinfectant: most detergents or bleach diluted 1:32 in water with washing-up liquid will kill herpes viruses. 
  • All known herpes viruses have the capacity to latently infect their hosts and recrudesce following stress, therefore reduction of environmental stress is recommended, especially in multicat environments such as breeding and boarding catteries and rescue shelters.  
  • Feline pheromone diffusers (Feliway) Pheromone analogue therapyNepeta cataria (catnip) and environmental enrichment can all help to reduce feline stress. 
  • Rescue shelters should strive to have natural, or positive pressure, ventilation to reduce aerosol transmission of aerosol-borne viruses. 

Vaccination

  • It is unknown if FHV-1 vaccines would confer any cross-protection against gammaherpesviruses. 

Other counter measures

  • FcaGHV1 is more prevalent in entire male cats over 3 years of age, therefore neutering may reduce risk of infection. 
  • Since both gammaherpesviruses have been found in the blood, avoid iatrogenic transmission by avoiding blood transfusions  Blood transfusion where possible. 
  • The effect of regular flea treatment for prevention of FcaGHV1 infection has not been assessed, but presumably would be beneficial. 
  • Avoid iatrogenic latent herpesvirus recrudescence by minimizing use of immunosuppressive drugs such as glucocorticoids, cyclosporine, and oestrous suppressants where possible.  
  • Optimize nutrition to support the immune system by ensuring adequate arginine levels. 
  • Since FcaGHV1 is found more often in cats immunosuppressed by concurrent infection with feline leukemia virus (FeLV) Feline leukemia virus or feline immunodeficiency virus (FIV), it is reasonable to speculate that steps taken to avoid those infections might decrease susceptibility to FcaGHV1. 
  • Presumably cats that do not have access to cattle or cow products are at less risk for BHV4 infection. 

Diagnosis

Useful samples

  • At time of writing (2020), it is unlikely that your local veterinary laboratory will offer testing for either FcaGHV1 or BHV4, although you may have access to a university laboratory with an interest in either of these conditions; in which case contact them to ask what samples they require prior to seeing your patient.
  • Whole blood in EDTA, or a piece of fresh lymphoma biopsy / fine needle aspirate (FNA) Fine-needle aspirate, post-mortem heart muscle, for PCR testing. 
  • Serum or plasma for serology Serology (however, although a negative test rules out FcaGHV1, the significance of a positive result is questionable, since many cats are seropositive). 
  • Lymphoma or heart muscle samples in 10% formol saline for in situ hybridization. 

Specimen storage

  • Store blood, biopsy, FNA material in sealed container in fridge (4°C) until posting and courier or post first class on day of sampling. 
  • Pathological samples will store indefinitely in 10% formol saline. 
  • Do not freeze bodies on which histopathology is to be conducted. 
  • PCR can be conducted on frozen pathological samples. 

Transport of samples

  • Fedex / courier or first class post blood samples / fresh material, do not post the day before a weekend or bank holiday. 
  • Label package to conform with RCVS recommendations, ie 'Pathological specimen - fragile. With care.' 

Field diagnosis

FcaGHV1 

  • At time of writing (2020) since FcaGHV1 is widely prevalent and its clinical significance unknown, it is unlikely that field diagnosis would be worthwhile, and anyway, most veterinary surgeons would not have access to an FcaGHV1 test. 
  • FcaGHV1 positive cats are 2.8 times more likely to be sick than negative cats: but was the FcaGHV causal or merely reactivated latent infection? 
  • FcaGHV1 is more likely to be found in hemoplasma infected cats. 
  • FcaGHV1 is more likely to be found in FIV, FeLV infected and immunosuppressed cats. 
  • FcaGHV1 investigation might be worthwhile in cats presenting with cardiorespiratory signs, especially hypertrophic cardiomyopathy Heart: hypertrophic cardiomyopathy
  • FcaGHV1 investigation may be worthwhile in cats presenting with lymphomas Lymphoma, especially of the gastrointestinal tract.  

BHV4 

  • No clinical signs have been attributed to BHV4 infection of cats other than lower urinary tract disease, which remains unproven. 

Laboratory diagnosis

FcaGHV1 

  • PCR of whole blood (the virus is found in the lymphocytes), intestine, fresh heart or lymphoma samples.  
  • In situ hybridization (ISH) to identify FcaGHV1 nucleic acid in heart muscle or lymphomas. 
  • FcaGHV1 has not been propagated in cell culture. 
  • Serology: persistently infected cats are seropositive. IFA, Western blot and ELISA tests have been developed using recombinant FcaGHV1 proteins, (Stutzman-Rodriguez et al, 2016) but are not available commercially. 

Bovine herpesvirus 4 (BHV4) 

  • PCR of urine is the most useful test for determining if BHV4 is involved in FLUTD cases. 
  • PCR of whole blood: viral DNA is found in peripheral blood leucocytes (Kruger et al, 2000). 
  • Serology: BHV4 antibodies were detected by an indirect immunofluorescent antibody (IFA) test in sera obtained from 31% (44/141) of cats with FLUTD and 23% (6/26) of control cats.  However, neutralizing antibodies were not detected in any of those cats. (Kruger et al, 1991). 

Further Reading

Publications

Refereed Papers

  • Recent references from PubMed and VetMedResource . 
  • Hendrikse L D, Kambli A, Kayko C, Canuti M, Rodrigues B, Stevens B, Vashon J, Lang AS, Needle D B, Troyer R M (2019) Identification of a Novel Gammaherpesvirus in Canada lynx (Lynx canadensis). Viruses 11(4) pii: E363. doi: 10.3390/v11040363 PubMed.  
  • Novacco M, Kohan N R, Stirn M, Meli M L, Díaz-Sánchez A A, Boretti  FS, Hofmann-Lehmann R (2019) Prevalence, Geographic Distribution, Risk Factors and Co-Infections of Feline Gammaherpesvirus Infections in Domestic Cats in Switzerland. Viruses 11(8), pii: E721. doi: 10.3390/v11080721 PubMed.  
  • Aghazadeh M, Shi M, Pesavento P A, Durham A C, Polley T, Donahoe S L, Troyer R M, Barrs V R, Holmes E C, Beatty J A (2018) Transcriptome Analysis and In Situ Hybridization for FcaGHV1 in Feline Lymphoma. Viruses 10(9) PubMed
  • Makundi I, Koshida Y, Endo Y, Nishigaki K (2018) Identification of Felis catus Gammaherpesvirus 1 in Tsushima Leopard Cats (Prionailurus bengalensis euptilurus) on Tsushima Island, Japan. Viruses 10(7),  pii: E378 PubMed.  
  • Marenzoni M L, Antognoni M T, Baldelli F, Miglio A, Stefanetti V, Desario C, Di Summa A, Buonavoglia C, Decaro N (2018) Detection of parvovirus and herpesvirus DNA in the blood of feline and canine blood donors. Vet Microbiol 224, 66-69. doi: 10.1016/j.vetmic.2018.08.030 PubMed
  • McLuckie A J, Barrs V R, Lindsay S, Aghazadeh M, Sangster C, Beatty J A (2018) Molecular Diagnosis of Felis catus Gammaherpesvirus 1 (FcaGHV1) Infection in Cats of Known Retrovirus Status with and without Lymphoma. Viruses 10(3) PubMed.   
  • Chiu E, Troyer R M, Lappin M R, VandeWoude S (201