They are composed of a core containing the double-stranded viral DNA genome, an icosahedral capsid surrounding the core, a tegument layer surrounding the capsid, and a lipid bilayer envelope from which glycoprotein spikes are protruding [ 6 , 7 ].
FeHV-1 primarily infects domestic cats, but lions and cheetahs are also susceptible [ 3 , 8 ]. In vitro , FeHV-1 replicates only in cells of feline origin. Grail et al. The genomic organization of both of these FeHV-1 strains was found to be similar to that of other varicelloviruses. We recently reported the first complete genomic sequence of FeHV-1, as well as the construction and characterization of a BAC clone containing the entire viral genome. A total of 78 open reading frames were predicted, encoding 74 distinct proteins.
The gene arrangement was found to be colinear with that of most other varicelloviruses whose genomes have been sequenced [ 14 ]. All alphaherpesviruses are considered to have a replication pattern that is similar to the one of HSV-1 [ 6 , 7 ]. FeHV-1 has previously been shown to contain 23 virion-associated proteins [ 15 ]. The examination of the recently derived complete sequence showed that the FeHV-1 genome in fact contains a total of 13 envelope glycoproteins [ 14 ].
Most studies on the function of FeHV-1 genes have been focused on the role of envelope glycoproteins [ 16 ], because of their predicted role in inducing protective host immune responses and, therefore, their potential for vaccine development.
FeHV-1 typically affects kittens and juvenile cats. Most kittens are protected by passive immunity until they are about 2 months of age. The pathogenesis of FHV-1 is based upon two different mechanisms. The first is that FeHV-1 is a cytolytic virus. Examples of its cytolytic effects are ulcerations in mucosae and the cornea. The second mechanism is immune-mediated, clinically manifesting itself as stromal keratitis. An important question related to this second pathogenetic mechanism is the source of the antigenic stimulation driving this reaction [ 17 ].
The main sources of FeHV-1 transmission are oronasal and ocular secretions from acutely infected cats. Viral transmission can also be associated with the reactivation of latency.
Kittens with residual passive immunity may not show clinical signs when exposed but become latently infected [ 18 ]. Following entry via the oronasal route, FeHV-1 replicates extensively in the mucosae of the upper respiratory tract and generally causes severe upper respiratory disease in susceptible animals.
The incubation period varies from 2 to 6 days. The primary replication sites of FeHV-1 include the mucosae of the nasal septum, turbinate, nasopharynx, conjunctivae, and upper trachea. Replication also takes place in tonsils and mandibular lymph nodes. Acute respiratory FeHV-1 infection is characterized initially by fever, inappetence, and sneezing, followed by serous nasal discharge, which can become mucopurulent after 5—7 days.
In addition, oral replication of the virus can result in excessive salivation and drooling of saliva. Occasionally coughing and dyspnea may occur. Oral ulceration, a typical feature of feline calicivirus infection, may occur as a result of FeHV-1 infection of the oral cavity but is uncommon [ 3 ].
The ocular manifestations associated with FeHV-1 infection have been reviewed by Gould [ 5 ]. In neonatal kittens ophthalmia neonatorum has been described and can lead to serious corneal damage.
Acute hyperemic conjunctivitis, leading to ocular discharge and chemosis, a feature of acute infection, occurs in association with upper respiratory signs. The formation of branched epithelial ulcers, referred to as dendritic ulceration, is a pathognomonic feature of acute ocular FeHV-1 infection.
Both dendritic and geographic corneal ulceration may also result from latency reactivation. FeHV-1 is primarily an upper respiratory and ocular pathogen, with only sporadic involvement of the lungs. Viremia levels are low, thought to be related to the natural temperature sensitivity of this virus, which would favor replication in the upper respiratory tract. Exposure of pregnant queens can lead to abortion, but infection with FeHV-1 infection is not a common cause of abortion in cats.
In neonatal kittens, the infection can generalize and is associated with neurological signs and a high mortality rate. A hallmark of alphaherpesvirus biology is that acute infection is followed by lifelong persistence of the viral genome in latent form in nervous and lymphoid tissues.
Latency and periodic reactivation of latency are integral parts of the lifecycle of alphaherpesviruses and important elements in their survival and transmission. The latency-reactivation cycle operationally consists of three major steps: establishment, maintenance, and reactivation. The establishment of latency by definition requires that the virus reaches the tissue in which latency will be established. This process starts during the acute phase of viral replication at peripheral mucosal sites.
Nerve endings of sensory nerves innervating viral replication sites take up viral particles and subparticles during this phase. These particles are transported within the axoplasm of the axons of these nerves by a process referred to as retrograde axonal transport.
When the virus reaches the sensory ganglia, it infects neurons and other cell types. This acute infection of ganglionic cell types lasts for approximately one week. Neurons are the cell type in which latency is established. In order to accomplish this, lytic gene expression is repressed, while the latency-associated transcript LAT is expressed, which yields several RNA species by splicing.
These multiple species are collectively referred to as LATs. Low level or sporadic transcription of immediate-early and early genes can occur but is not sufficient to initiate a productive infection. No infectious virions can be detected in the ganglia during latent infection. During the maintenance phase of latency, the viral DNA is present in the neurons in an episomal form.
The viral DNA is not totally static during the maintenance phase of latency, but transcriptional activity of the genome is limited to a region referred to as the latency-associated transcript or LAT. The maintenance phase of latency is reversible. In other words, under the influence of certain natural or pharmacological stimuli, the reactivation of latent viral DNA can occur.
Infectious virus can be detected again by virus isolation or PCR from nasal, oral, or ocular swabs. Usually the clinical signs associated with the reactivation process are significantly milder than those seen during the primary infection, and reactivation can certainly be asymptomatic. Virus shedding resulting from reactivation is also typically at a lower level and of shorter duration than seen during primary infection. However, reactivating virus can still be a significant source of exposure and primary disease in fully susceptible hosts that are in close contact with the animal in which reactivation took place.
Reactivation occurs in only a small subset of latently infected neurons, typically less than 0. Latently infected neurons in which reactivation took place do not survive. This explains why sensory deficits are not associated with reactivation in sensory nerve ganglia.
Since the reservoir of latently infected neurons remains large under these conditions, repeated reactivation can take place throughout the life of the host. Our current understanding of the regulation of latency is derived primarily from studies on HSV-1 and BoHV-1 [ 20 — 22 ].
The following summary is derived primarily from an excellent very recent review of HSV-1 latency by Perng and Jones [ 20 ]. Acute infection of trigeminal ganglia neurons produces toxic gene expression products that make them vulnerable to damage and death. In addition, cellular DNA damage induced by viral replication stimulates the mitochondrial pathway of apoptosis. Herpesviruses try to counteract apoptosis and thus enhance their replicative ability, by encoding several antiapoptotic genes, one of which is the LAT gene.
Since there is redundancy in the viral antiapoptotic capabilities during the acute phase, apoptosis of neurons during this phase is prevented fairly efficiently.
It is very important that apoptosis is prevented also during the establishment and maintenance stage of latency. This is especially crucial in permissive neurons, in which extensive viral replication has taken place during the acute phase.
A mechanism by which LAT-encoded miRNA regulates apoptosis is targeting of transforming growth factor beta, a potent inducer of apoptosis [ 23 , 24 ]. It is important to understand the interactions between the latent viral genome and the neuron that lead to reactivation, because this is a prerequisite to ultimately controlling this process.
LAT plays an important role in the in vivo reactivation of latency. In experimental studies it has been shown that spontaneous reactivation is severely impaired if the LAT gene is deleted.
Thompson et al. Prior to establishment of latency virus replication takes place in permissive neurons. In susceptible cells at mucosal surfaces VP16, a component of virions entering the cell, combined with cellular factors, activates the immediate early genes. Axonal transport of VP16 into neurons is inefficient, which would promote latency. In order for VP16 to initiate lytic infection, it needs to be synthesized de novo , a process which requires that neuronal inhibition be overcome.
Very interestingly, the LAT locus is considered to express riboregulators that mediate synthesis of VP It has been shown that, in the absence of LAT transcription, half of the neurons destined to be latently infected instead enter the lytic cycle and die.
In contrast when repression is overcome, neurons become lytically infected, and the infectious virus produced spreads both within the ganglia and back to the mucosal surface where infection was initiated. The goal of lytic infection is to increase the number of latently infected cells. Stress, leading to reactivation, is hypothesized to increase the novo production of VP16 by a mechanism that is still under investigation.
The VP16 produced then initiates a feedback loop with the IE genes and results in viral reactivation in a very limited number of latently infected neurons. Viral antigen production in trigeminal ganglia increases until 3 days after infection but is no longer detectable at 7 days after infection. Persistence of immune effector cells in trigeminal ganglia TG implies that low levels of viral proteins are expressed and that an immune response occurs.
In a mouse HSV-1 model, it has been demonstrated that viral DNA replication, transcription, and viral protein production take place in 1 neuron per 10 TG.
Two mechanisms by which these infiltrating cells prevent reactivation are the production of gamma interferon and lymphocyte-mediated cytotoxicity. The trigeminal ganglion is considered a primary site of latency for FeHV-1 although recent studies implied other tissues as potential sites [ 26 , 27 ].
Spontaneous reactivation is possible but does not occur frequently. More commonly leading to the reactivation of latent FeHV-1 is the result of environmental or physiological stresses, such as changes in housing or lactation.
The lag phase between the stressor leading to reactivation and the actual shedding of infectious virus is about 4—11 days, and virus excretion lasts for approximately 6 days on average.
Virus excretion by cats in which a reactivation event took place ranges from 1—13 days [ 29 , 31 ]. During this time infectious virus can be demonstrated in ocular and oronasal secretions. The reactivation can be either asymptomatic or associated with clinical signs. Symptomatic reactivation is referred to as recrudescence. Reactivation of latent viral DNA in adult cats can lead to corneal ulceration, accompanied by varying degrees of conjunctivitis [ 32 ].
Since herpetic stromal keratitis caused by HSV-1 is the leading cause of infectious blindness in industrialized countries, ocular infection of FeHV-1 in cats is considered a very good natural host model. Infectious virus is carried by anterograde axonal transport to peripheral tissues, usually to cells at or near the site of initial infection, and is a potential source of viral transmission [ 6 , 7 ]. The role of reactivation in the epidemiology of alphaherpesviruses is directly related to the frequency by which it takes place.
Some herpesviruses, including FeHV-1, reactivate much more easily than others from the latent state, both under natural and experimental conditions. The ease by which latent FeHV-1 DNA is reactivated is an important element in the justification of FeHV-1 infection of cats as a natural host model to study the molecular pathogenesis of herpesvirus latency and approaches to prevent it. Clinically, there is an overlap between the symptomatology of acute FeHV-1 and feline calicivirus FCV , another major respiratory disease of cats.
Distinguishing features of FeHV-1 infection are high fever and corneal ulcerations. In contrast, ulcers of the tongue, palate, and pharynx are more typical or encountered more frequently in calicivirus infections. The most common laboratory diagnostic methods to demonstrate the presence of FeHV-1 or viral components in tissue homogenates or swabs include the direct fluorescent antibody FA test, virus isolation VI , and PCR [ 3 , 5 , 18 ].
Fluorescent antibody testing is performed on conjunctival or corneal tissue. This test is far less commonly used now than it used to be. Topical fluorescein, used to visualize ulcers, should be avoided prior to collecting samples. Laboratory diagnosis of acute FeHV-1 is now most commonly performed by virus isolation VI or PCR, using oronasal and conjunctival swab extracts as the samples.
VI detects infectious virus and has been the laboratory diagnostic gold standard [ 4 , 28 ]. The assay was determined to be very specific for FeHV-1, and its detection limit was between 0. Infectious virus titers and viral DNA correlated over a wide dilution range. Early during infection, referred to as phase 1, the correlation between virus titers and qPCR signals was very high. Next, during so called phase 2, a rapid decline in infectious virus titers was seen, while the qPCR signals remained high.
During the final phase, referred to as phase 3, infectious virus was no longer detectable, and the quantitative PCR signals were also declining. Analysis of the combined virus detection and qPCR results on 20 clinical samples allowed the authors to reliably define the phase of the infection during which the samples had been collected.
Realizing the cost of combined testing, it was suggested to test consecutive samples by qPCR to accomplish this goal. Maggs [ 4 ] pointed out 3 aspects of laboratory diagnosis of FeHV-1 that can be very frustrating for the clinician. Whereas the confirmation of acute FeHV-1 is not always required, it is important to confirm that chronic lesions are caused by FeHV Unfortunately, the detection of FeHV-1 or viral components in these lesions can be difficult.
The second aspect of laboratory diagnosis that leads to misinterpretations is the fact that FEHV-1 or viral l DNA can be detected in samples from clinically normal cats. It was pointed out that the detection of FeHV-1 or its components can be coincidental, consequential, or causal.
Differentiating between these possibilities is obviously important. Virus neutralizing antibody titers are determined by VN tests, which are commonly used to detect prior infection or the efficacy of vaccination. Virus neutralizing antibodies can be low and slow to develop. As pointed out by Dawson et al.
As is the case for many viral infections, supportive therapy is being advised. Broad spectrum antibiotics that achieve good penetration into the respiratory tract should be administered in all acute cases to prevent secondary bacterial infections.
Intake of food that is palatable and flavorful is also important, since infected cats develop anorexia from the loss of their sense of smell or, less commonly, the presence of ulcers in the oral cavity.
In cats with severe clinical signs, the restoration of fluids, electrolytes, and acid-base balance is required, preferably intravenously. Nasal decongestants, mucolytic drugs, and nebulization with saline can all ameliorate clinical signs. Eye drops or ointments, when used, should be administered several times a day.
Antiviral therapy consists of topically or systemically administered antivirals or the use of adjunctive therapies. Comparison of 8 antiviral drugs administered topically demonstrated that the highest efficacy was obtained with trifluridine, based upon its potency and corneal penetration.
Second in effectiveness was idoxuridine, which has a lower cost and appears to be less irritating [ 4 ]. They are converted into triphosphates by viral thymidine kinase and other host enzymes in infected cells and competitively inhibit viral DNA polymerase. This prevents DNA chain elongation [ 35 ] and, as a result, disrupts viral replication.
The use of these agents against FeHV-1 infection has been largely limited to topical administration. First generation nucleoside analogues, including acyclovir and its prodrug valacyclovir, have little efficacy against FeHV-1 in vitro and moderate effect in vivo.
More importantly, when administered systemically they produce serious side effects in cats, including myelosuppression, hepatotoxicity, and nephrotoxicity at therapeutic levels [ 36 , 37 ]. Acyclovir, ganciclovir, and idoxuridine are also suggested for topical use. It was noted that, except for acyclovir, there is a lack of controlled in vivo efficacy study for these agents in the literature [ 18 ].
The efficacy of topical application of cidofovir on primary ocular FeHV-1 infection has been demonstrated [ 38 ]. Although the study wasn't controlled, oral administration of famciclovir has been reported to be safe and efficacious in treating ocular signs, cutaneous disease, and rhinosinusitis induced by FeHV-1 infection [ 39 ]. Adjunctive therapies that are used to treat FeHV-1 infection are L-lysine, lactoferrin, and interferons.
L-lysine is an antagonist of arginine; the latter has been shown to be essential for HSV-1 and FeHV-1 protein synthesis [ 40 ]. Treatment with L-lysine, therefore, decreases viral replication and has been shown to have some inhibitory effect against both human herpesvirus and FeHV-1 infection. An issue with low dietary arginine concentrations is the pronounced susceptibility of cats to arginine deficiency [ 40 , 42 ].
Oral supplementation with L-lysine reduces the severity of experimentally induced FeHV-1 conjunctivitis [ 42 ] and ocular virus shedding associated with the reactivation of latent infection [ 40 ]. It was suggested for use early in acute disease or as a means of reducing the severity of disease and virus shedding at times of stress [ 3 ]. It has been demonstrated that L-Lysine is safe at relatively high oral dose levels. Lactoferrin is a mammalian iron-binding glycoprotein.
Interferons are cytokines released by white blood cells and interfere with viral cell-to cell spread. Primary FeHV-1 infection induces both humoral and cellular immune responses. Active immunity induced by natural FeHV-1 infection or immunization protects cats from the disease, but not from infection. Mild clinical signs have been observed upon reexposure as soon as days after the primary infection [ 18 , 44 , 45 ]. Virus neutralizing antibody titers are generally low and in some cases undetectable after primary infection; although after further exposure to virus, they tend to rise to more moderate levels and thereafter remain reasonably stable [ 3 , 46 ].
Since FeHV-1 targets the eye and upper respiratory tract, mucosal immune responses also play a significant role [ 47 ]. Passive immunity persists for 2 to 10 weeks, depending upon colostrum concentration and intake. Some kittens with low levels of maternally derived antibodies that are exposed to field virus may develop subclinical infection and latency [ 48 ].
Alternatively, such kittens would also respond to early vaccination. Conversely, in some kittens maternally derived antibodies are high enough to still be at interfering levels at 12—14 weeks of age [ 3 , 49 ]. The ABCD panel recommends an initial two-dose vaccination regimen: the first dose being given at 9 weeks of age and the second at 12 weeks of age. This is followed by yearly boosters [ 18 ]. The American Association of Feline Practitioners Feline Vaccine Advisory Panel advises that the primary immunization dose should be given as early as 6 weeks of age, with additional doses every 3 to 4 weeks until 16 weeks of age.
If a specific diagnosis is required, ocular or oral swabs can be submitted to a veterinary laboratory where the virus can be grown in culture or, more commonly, detected by PCR a molecular technique for detecting the genetic material of the virus. Evidence of the virus may also be present in biopsies and can be useful for the diagnosis of FHV-associated dermatitis skin infection.
FHV infections are frequently complicated by secondary bacterial infections, so supportive treatment with antibiotics is usually required. Good nursing care is critical and cats may need to be hospitalised for intravenous fluid therapy and nutritional support in severe cases. Steam inhalation or nebulisation may help in cases of severe nasal congestion and as the cat will not be able to smell food well, using tinned or sachet foods that are gently warmed will help. Unlike FCV, with FHV infection certain anti-viral drugs are available and can be very helpful in managing the clinical manifestations of disease.
In colonies of cats, any cat showing clinical signs should be isolated if at all possible, and strict hygiene should be ensured with disinfection, and use of separate feeding bowls, litter trays, implements etc, careful washing of hands, use of separate or disposable apron etc. Vaccination for FHV is important for all cats. Two or three injections are recommended in kittens, starting at around 8 weeks of age. Cats should receive a booster at a year of age, and after that should receive further booster vaccines every 1—3 years.
Vaccination does not necessarily prevent infection with FHV but will greatly reduce the severity of clinical disease. Unlike FCV, there is effectively only one strain of FHV, so vaccination is not complicated by the existence of different strains.
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Pregnant cats or those suffering from a lowered immunity due to a pre-existing disease are also at higher risk. Symptoms and Types Some infected cats can remain without symptoms, yet act as carriers and spread the infection to other non-infected cats. The following symptoms may also be sporadic in a FHV-1 carrier: Sudden, uncontrollable attacks of sneezing Watery or pus containing nasal discharge Loss of sense of smell Spasm of the eyelid muscle resulting in closure of the eye blepharospasm Eye discharge Inflammation of the conjunctiva of the eye conjunctivitis Keratitis inflammation of the cornea causing watery painful eyes and blurred vision Lack of appetite Fever General malaise Loss of pregnancy Cause This condition is caused by an infection with the feline herpesvirus 1 infection.
Treatment Broad spectrum antibiotics will be prescribed for the prevention or treatment of secondary bacterial infections. Living and Management It is important to minimize or remove any stress, which may lengthen the course of the disease.
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