Feline Herpesvirus Latency and Reactivation
Overview and Taxonomy of Feline Herpesvirus-1 (FHV-1) Latency
Feline herpesvirus type 1 (FHV-1) is the etiological agent of feline viral rhinotracheitis, a highly contagious and globally prevalent disease of domestic and wild felids. The virus exemplifies the defining biological hallmark of the subfamily Alphaherpesvirinae: the capacity to establish lifelong latency in sensory neurons following acute infection, with periodic reactivation leading to recrudescent clinical disease and viral shedding. This section provides a comprehensive overview of FHV-1 latency, beginning with its taxonomic classification and progressing through the molecular and cellular mechanisms that govern the establishment, maintenance, and reactivation of the latent state. A deep understanding of these processes is essential for interpreting clinical patterns, designing effective antiviral strategies, and developing safer vaccines, goals that remain at the forefront of feline medicine.
Taxonomic Classification and Phylogenetic Context
FHV-1 is classified within the family Herpesviridae, subfamily Alphaherpesvirinae, genus Varicellovirus [1, 6, 12]. Its official species designation is Felid alphaherpesvirus 1 (FeHV-1). The virus is a double-stranded DNA virus with a genome of approximately 126–135 kbp, encoding at least 78 open reading frames, many of which are conserved among alphaherpesviruses. Phylogenetically, FHV-1 is most closely related to other varicelloviruses of veterinary importance, including bovine herpesvirus type 1 (BoHV-1) and type 5 (BoHV-5), as well as equine herpesvirus type 1 (EHV-1). This relatedness is reflected in shared structural proteins (e.g., glycoproteins gB, gD, gE, gI), common mechanisms of neurotropism and latency, and even cross-reactivity in serological assays.
The genetic and antigenic diversity of FHV-1 is remarkably limited compared to other feline respiratory viruses such as calicivirus [12]. Field isolates exhibit high sequence conservation in essential glycoprotein genes (e.g., gD and gE), a finding confirmed by comparative sequence analyses of isolates originating from domestic cats and non-domestic felids, such as snow leopards (Panthera uncia) [3, 8]. This genetic stability implies that the virus has adapted efficiently to its feline host, with latency representing a stable evolutionary strategy that ensures lifelong persistence within individual animals and facilitates transmission to naive hosts during episodes of reactivation.
Latency as a Core Biological Strategy
Following primary infection of the upper respiratory tract and ocular mucosa, FHV-1 replicates extensively in epithelial cells of the nasal turbinates, conjunctiva, and cornea, and in sensory neuronal cells [5, 6]. Within days, the virus enters the termini of sensory nerves innervating the infected mucosae and travels via retrograde axonal transport to the cell bodies of the trigeminal ganglia (TG), where it establishes latent infection [1, 5, 9]. During latency, the viral genome persists as a circular episome within the neuronal nucleus, with a highly restricted pattern of gene expression. Productive replication is silenced; no infectious virions are produced. This state is lifelong, and the vast majority of cats that recover from acute FHV-1 infection become asymptomatic, lifelong carriers [10].
The precise molecular mechanisms governing the establishment and maintenance of FHV-1 latency are incompletely understood, but parallels with human herpes simplex virus (HSV) latency are well recognized. Viral factors such as thymidine kinase (TK), glycoprotein E (gE), and glycoprotein I (gI) are critical for efficient reactivation and, in some cases, for initial entry into the latent state. Experimental deletion of TK, gE, and gI genes severely impairs the ability of recombinant FHV-1 to establish latency in vivo, as demonstrated by dramatically reduced viral loads in trigeminal ganglia after challenge [7]. Similarly, deletion of the serine/threonine protein kinase (PK) gene and double deletion of gE and TK attenuate viral replication in feline respiratory epithelial cells and alter cytokine responses, suggesting that these genes modulate the host immune environment in ways that favor latency [4]. The latency-associated transcript (LAT) region, a hallmark of alphaherpesvirus latency, has been identified in the FHV-1 genome, though its precise role in maintaining latency and facilitating reactivation remains an active area of investigation.
Reactivation Triggers and Epidemiology of Shedding
The ability to reactivate from latency is the most clinically relevant feature of FHV-1 infection. Stress, broadly defined as any physiological, environmental, or pharmacological perturbation, is the most potent trigger for reactivation. Common stressors include weaning, overcrowding, poor nutrition, concurrent disease, corticosteroid administration, and, notably, the novel environment of an animal shelter [10, 11]. The epidemiological significance of stress-induced reactivation is vividly illustrated by a landmark study of cats entering shelters: on entry, only 4% of cats were shedding FHV-1, but after one week in the shelter environment, 52% were shedding [11]. This dramatic 13‑fold increase was attributed primarily to reactivation of latent infections, with a smaller contribution from new infections. The speed of amplification underscores how environmental stress can rapidly convert a population of clinically healthy carriers into a highly infectious cohort.
Other triggers include co-infection with other pathogens, particularly feline calicivirus (FCV) and Bordetella bronchiseptica, and immunosuppressive conditions such as feline leukemia virus (FeLV) or feline immunodeficiency virus (FIV) co-infection [1]. Exogenous glucocorticoids are a well‑established experimental tool to induce reactivation, and their clinical use (e.g., for treating inflammatory conditions) can inadvertently cause recrudescence of FHV-1 disease [10]. In non‑domestic felids, natural stress events such as captivity, transport, or illness have been linked to lethal reactivation events. For example, a captive snow leopard that died from severe rhinotracheitis and interstitial pneumonia was determined to have experienced reactivation of a latent FHV-1 infection acquired from a domestic cat [3, 8]. Such cases highlight the broad host range of FHV‑1 within the family Felidae and the conservation of latency mechanisms across species.
Clinical Implications of Latency
Reactivation results in the production of infectious virus, which travels anterogradely along sensory axons back to the original mucosal sites, the nasal cavity, conjunctiva, and cornea, inducing recurrent clinical signs identical to those of primary infection, albeit often less severe. Ocular signs, in particular, dominate the reactivation phenotype: conjunctivitis, keratitis, and the characteristic dendritic corneal ulcers are hallmark manifestations [1, 9]. Chronic, recurrent keratitis can lead to corneal sequelae such as sequestration, stromal keratitis, and symblepharon, which are among the most challenging complications in feline ophthalmology [9]. Systemic antiviral therapy with famciclovir and topical agents such as cidofovir are employed to control acute episodes, but they do not eliminate the latent viral reservoir [1, 2]. Vaccination with currently available modified‑live vaccines reduces clinical severity but does not prevent infection, latency establishment, or subsequent reactivation [4, 7]. This limitation has spurred research into rationally attenuated vaccine candidates, such as the TK/gI/gE‑deleted recombinant FHV‑1 (WH2020‑ΔTK/gI/gE), which not only provide superior protection against challenge but also exhibit a reduced propensity to establish latency in the trigeminal ganglia [7].
Comparative and Model‑Based Perspectives
FHV‑1 infection of the cat is widely recognized as a valuable natural host model for alphaherpesvirus pathogenesis, particularly for understanding latency and reactivation mechanisms relevant to human herpes simplex virus and varicella‑zoster virus [5, 6]. The feline model offers advantages over rodent models because the virus is naturally adapted to its host, the anatomic sites of latency (trigeminal ganglia) are identical to those in humans, and the clinical endpoints (respiratory and ocular disease) are directly analogous to those seen in human herpetic keratitis and nasal herpes. The availability of well‑characterized viral mutants, defined reactivation protocols, and quantitative PCR assays to measure viral DNA in ganglia and secretions makes FHV‑1 an indispensable tool for translational research [4, 5]. Moreover, the WHO and WOAH recognize the importance of controlling FHV‑1 in both domestic and wild felids due to its impact on animal welfare and conservation efforts.
In summary, the taxonomy of FHV‑1 places it firmly within the alphaherpesvirus lineage, and its latency biology, establishment in the trigeminal ganglia, lifelong persistence, and stress‑induced reactivation, is the central pillar of its pathogenicity. Understanding the molecular determinants that regulate these processes, from the essential roles of TK, gE, gI, and PK to the environmental triggers that perturb the latent state, is fundamental to improving clinical management and vaccine development. The following sections will delve deeper into the specific molecular pathways, immune interactions, and therapeutic strategies that emerge from this foundational understanding of FHV‑1 latency.
Molecular Pathogenesis of FHV-1 Latency Establishment and Reactivation
The capacity of feline herpesvirus type 1 (FHV-1) to establish lifelong latency within the sensory neurons of its host represents the single most critical feature of its pathobiology, underpinning the virus’s persistence in feline populations worldwide and its recalcitrance to eradication efforts. This phenomenon, shared with other alphaherpesviruses such as human herpes simplex virus (HSV) and varicella-zoster virus (VZV), transforms an acute, often self-limiting respiratory and ocular infection into a chronic, recurrent condition with profound implications for individual animal welfare and population-level disease management [1, 6]. The molecular choreography governing the transition from lytic replication to quiescent latency, the maintenance of the latent genome within the neuronal nucleus, and the eventual reactivation in response to physiological stress is a complex interplay of viral gene regulation, host cellular signaling, and epigenetic control. Understanding this molecular pathogenesis at a granular level is not merely an academic exercise; it is the foundation upon which rational vaccine design, antiviral therapy, and strategies for preventing recrudescence are built.
The Neurotropic Niche: Entry into the Trigeminal Ganglia
Following primary infection of the upper respiratory tract, conjunctiva, and corneal epithelium, FHV-1 exploits the axonal transport machinery of sensory neurons to establish a foothold in the peripheral nervous system. The virus gains access to the nerve endings that innervate the mucosal surfaces of the nasal turbinates, nasopharynx, and cornea. The primary site of latency for FHV-1, as documented extensively in both experimental and natural infections, is the trigeminal ganglia (TG) [1, 5, 6]. This is a conserved neuroanatomic target for many alphaherpesviruses, including HSV-1 in humans and bovine herpesvirus type 1 (BoHV-1) in cattle. The virus is transported via retrograde axonal transport along microtubules, a process mediated by the viral tegument proteins that interact with host dynein motor complexes. Once the viral capsid reaches the neuronal soma, the viral genome is released into the nucleoplasm. Critically, this does not automatically initiate a lytic cascade. Instead, the virus confronts a cellular environment that is fundamentally different from the permissive, rapidly dividing epithelial cells of the mucosa. The neuron is a long-lived, post-mitotic cell with a highly specialized transcriptional program, and it presents a formidable barrier to the viral lytic cycle. The decision between lytic replication and latency is a stochastic and regulated event, influenced by the multiplicity of infection, the activation state of the neuron, and the immediate-early viral gene expression dynamics. In the context of FHV-1, the establishment of latency is the default pathway for virions that successfully reach the TG, as evidenced by the universal detection of latent viral DNA in the TG of seropositive cats [5, 10].
The Molecular Switch: Lytic Cycle Arrest and the Latent Transcriptome
The hallmark of FHV-1 latency is the profound restriction of viral gene expression. During the lytic cycle, the viral genome is transcribed in a tightly regulated temporal cascade: immediate-early (IE) genes, such as the major transactivator (likely homologous to HSV ICP4), are expressed first, followed by early (E) genes encoding enzymes like thymidine kinase (TK) and the replication machinery, and finally late (L) genes encoding structural proteins like glycoproteins gC, gD, gE, and gI [4, 7]. During latency, this cascade is aborted. The viral genome persists as a circular episome within the neuronal nucleus, associated with histones in a chromatin structure that is heavily repressed. The only abundant viral transcripts detected during latency are the latency-associated transcripts (LATs). While the precise FHV-1 LAT has not been as exhaustively characterized as the HSV-1 LAT, the functional parallels are compelling. The LAT region is thought to produce non-coding RNAs that act as molecular sponges for host microRNAs (miRNAs) or directly modulate chromatin modifying complexes to suppress lytic gene expression. The primary function of the LAT is to maintain the lytic gene promoters in a silenced, heterochromatic state, preventing the expression of the IE gene product that would otherwise trigger the entire lytic cascade. This epigenetic silencing is a dynamic process, involving the recruitment of histone deacetylases (HDACs) and other repressive complexes to the viral genome. The viral genome is thus maintained in a poised but inactive state, ready to re-enter the lytic cycle upon receipt of the appropriate cellular signals.
The Role of Viral Gene Products in Latency Establishment and Maintenance
The ability of FHV-1 to establish latency is not merely a passive consequence of neuronal infection; it is an active process mediated by specific viral gene products. The deletion of certain viral genes has been shown to profoundly alter the virus’s ability to establish or maintain latency, or to reactivate efficiently. For instance, the thymidine kinase (TK) gene, an early enzyme essential for nucleotide metabolism in non-dividing cells, is crucial for viral replication in neurons. TK-deleted mutants are severely attenuated and show a significantly reduced capacity to establish latency or reactivate, making TK deletion a cornerstone of rationally designed modified-live vaccines (MLVs) [4, 7]. Similarly, glycoprotein E (gE) and glycoprotein I (gI) form a heterodimer that functions as an Fc receptor for host immunoglobulin G, a mechanism of immune evasion that also plays a role in neuroinvasion and cell-to-cell spread. Deletion of gE, either alone or in combination with TK, results in a virus that is impaired in its ability to replicate in the TG and to reactivate from latency [4, 7]. The serine/threonine protein kinase (PK) encoded by FHV-1, homologous to HSV US3, is another critical determinant. This kinase is a multifunctional regulator that phosphorylates host proteins to block apoptosis, inhibit the interferon response, and modulate the cytoskeleton. In feline respiratory epithelial cells (FRECs), a PK-deletion mutant showed significantly reduced replication and failed to induce the same pattern of cytokine dysregulation seen with wild-type virus, including the suppression of IL-8 and KC (neutrophil chemoattractants) [4]. This suggests that PK is not only a virulence factor for acute disease but also contributes to the establishment of a favorable environment for latency by subverting the innate immune response within the infected neuron. The construction of a TK/gI/gE triple-deletion mutant using CRISPR/Cas9 technology represents a significant advance, demonstrating that the removal of these specific virulence and immune evasion genes yields a virus that is severely impaired in its ability to colonize the TG and reactivate, while retaining strong immunogenicity [7].
The Trigger: Stress, Glucocorticoids, and the Reactivation Cascade
Reactivation from latency is the process by which the dormant viral genome re-enters the lytic cycle, leading to the production of infectious virions that are transported anterogradely back down the axon to the peripheral mucosa, resulting in viral shedding and, frequently, recrudescent clinical disease [1, 6, 10]. The most potent and well-documented triggers for FHV-1 reactivation are physiological and environmental stressors. These include concurrent illness, immunosuppression, transportation, boarding, overcrowding, poor nutrition, and, most notably, the administration of corticosteroids [1, 10, 11]. The molecular link between stress and reactivation is the glucocorticoid receptor (GR) signaling pathway. Stress induces the release of cortisol, which binds to the GR in the cytoplasm of the latently infected neuron. The activated GR translocates to the nucleus, where it functions as a transcription factor. Crucially, the FHV-1 genome, like that of other alphaherpesviruses, contains glucocorticoid response elements (GREs) within its regulatory regions. The binding of the activated GR to these GREs is believed to directly or indirectly disrupt the repressive chromatin environment of the latent genome, initiating the expression of the IE genes. This kickstarts the lytic cascade, leading to the production of viral particles. The speed and efficiency of this process are remarkable. Epidemiological data from shelter environments demonstrate this phenomenon starkly: FHV-1 shedding rates can increase from as low as 4% upon entry to over 50% within just one week, a surge attributed not only to new infections but overwhelmingly to the reactivation of latent infections in stressed animals [11]. This rapid amplification of viral shedding in high-density, high-stress environments like shelters is a primary driver of FHV-1 transmission and disease outbreaks.
The Immune Landscape of Reactivation: A Delicate Balance
The establishment and maintenance of latency are not solely dependent on viral factors; the host immune system plays a continuous and essential role in keeping the virus in check. The latent viral genome is not invisible to the immune system. Periodic, abortive reactivation events likely occur at a low frequency, producing small amounts of viral proteins that are recognized by resident T cells in the TG. This constant immune surveillance, particularly by CD8+ cytotoxic T lymphocytes (CTLs) and the production of interferon-gamma (IFN-γ), is critical for suppressing full-blown reactivation. A decline in cell-mediated immunity, whether due to age, concurrent infection (e.g., feline leukemia virus or feline immunodeficiency virus), or iatrogenic immunosuppression, lowers the threshold for reactivation. This is why immunosuppressive doses of corticosteroids are such a reliable experimental trigger for reactivation: they directly induce the lytic cycle via the GR pathway while simultaneously suppressing the very T-cell responses that would normally contain the nascent reactivation event. The reactivation process itself is also accompanied by a specific pattern of immune modulation. During acute infection, FHV-1 has been shown to modulate the expression of key cytokines, including suppressing IL-8 and KC, which are crucial for neutrophil recruitment, and altering the balance of IFN-α, TNF-α, IL-1β, IL-10, and TGF-β [4]. This immunomodulatory capacity, mediated by virulence factors like PK and gE, likely contributes to the virus’s ability to reactivate and replicate in the face of an ongoing immune response, allowing for a window of shedding before the host can mount an effective recall response. The reactivation event is thus a race between viral replication and the host’s anamnestic immune response, a race that the virus frequently wins, leading to the characteristic recurrent episodes of conjunctivitis, keratitis, and rhinitis seen in latently infected cats [1, 9]. The molecular details of this tug-of-war, particularly the role of specific viral proteins in evading the intrinsic and innate immune defenses of the neuron, remain a rich area of investigation with direct relevance to the development of therapies aimed at preventing reactivation.
Epidemiology of FHV-1 Latency and Reactivation Risk Factors
The global distribution of FHV-1 is a testament to its evolutionary success as an alphaherpesvirus, its epidemiology inextricably linked to the ubiquitous nature of latency and the specific ecological and physiological triggers that govern reactivation. FHV-1 is not merely a pathogen of acute disease; it is a lifelong resident of the feline host, and its prevalence within populations is a dynamic reflection of the delicate balance between viral latency and the forces that disrupt it. Understanding the epidemiology of this latent state and the precise factors that precipitate reactivation is paramount for controlling disease at both individual and population levels, particularly within high-density environments. This analysis delves into the quantitative data and mechanistic insights that define the landscape of FHV-1 latency and its reactivation.
Global Prevalence and the Latent Reservoir
FHV-1 is a leading cause of viral upper respiratory tract disease in cats worldwide, responsible for approximately 50% of all viral upper respiratory infections [7]. Its seroprevalence is exceptionally high, a direct consequence of the virus’s ability to establish lifelong latency. Following primary infection, the virus travels via retrograde axonal transport to establish a quiescent state within the sensory neurons of the trigeminal ganglia [1, 5, 6]. This neurotropic sanctuary renders the host a permanent carrier, creating an invisible reservoir that perpetuates the virus within populations. The true prevalence of the latent carrier state is far greater than the prevalence of active disease. While serological surveys indicate widespread exposure, with most adult cats possessing antibodies [1], this immunity is often non-sterilizing, failing to prevent the establishment of latency or subsequent reactivation [4]. This reality means that in any population of cats, particularly those in multi-cat households, shelters, or catteries, a significant proportion harbor latent FHV-1.
The Shelter Environment: A Sentinel for Reactivation Dynamics
Perhaps the most compelling epidemiological data on FHV-1 reactivation comes from studies of cats entering shelter environments. These settings serve as natural laboratories, demonstrating the potent interplay between stress and viral resurgence. In a seminal study of cats relinquished to shelters, the prevalence of FHV-1 shedding upon entry was remarkably low, only 4%, and was predominantly observed in juvenile cats [11]. This low baseline reflects a state of relative viral suppression in the home environment. However, the shelter environment acts as a profound catalyst. Within just one week of confinement, the rate of FHV-1 shedding skyrocketed to 52% [11]. This dramatic, ten-fold increase is not solely attributable to new infections spreading from the small number of initial shedders. The rapidity and magnitude of the increase strongly indicate a massive wave of reactivation from latency in the resident cat population, triggered by the acute stress of relinquishment, novel environment, social disruption, and potential nutritional compromise [11]. This finding underscores a critical epidemiological principle: the population-level burden of FHV-1 is dynamically shaped not by the steady state of chronic carriers, but by the frequency and intensity of reactivation events. The shelter environment serves as a worst-case scenario, but these same principles apply, albeit with lower intensity, to any situation that compromises the host's physiological equilibrium.
Specific Reactivation Risk Factors: A Multifactorial Model
The transition from a latent, transcriptionally silent genome to an active lytic cycle is not a random event. It is orchestrated by a cascade of host physiological signals, primarily involving stress hormones and immune modulation. The literature identifies several discrete, yet often overlapping, risk factors.
Physiological Stress and Corticosteroid Induction: The most well-documented and experimentally reproducible trigger for FHV-1 reactivation is stress, often mediated through endogenous or exogenous corticosteroids. The European Advisory Board on Cat Diseases (ABCD) guidelines explicitly state that stress or corticosteroid treatment may lead to virus reactivation and shedding [10]. This is a direct parallel to the mechanism seen in other alphaherpesviruses, where glucocorticoid response elements (GREs) in the viral genome can directly enhance lytic gene expression [1, 9]. In clinical practice, this means that any significant stressor, boarding, surgery, illness, social conflict, or a change in routine, can reactivate the virus. The use of exogenous corticosteroids, whether for anti-inflammatory or immunosuppressive purposes, is a particularly potent and iatrogenic risk factor that must be weighed carefully in any cat with a known history of FHV-1 [10].
Immunosuppression and Concurrent Disease: The immune system is the primary sentinel controlling latent FHV-1. Any condition that compromises cell-mediated immunity or the robust interferon response can tip the balance in favor of reactivation. This is why FHV-1 is particularly problematic in young kittens with developing immune systems and in immunocompromised or aged cats [1]. Concurrent infections serve as major co-factors. The ABCD guidelines highlight that FHV-1 is often associated with feline calicivirus and secondary bacterial infections [10]. The immune dysregulation caused by a primary viral infection, such as feline leukemia virus (FeLV) or feline immunodeficiency virus (FIV), can create a permissive environment for FHV-1 reactivation. Furthermore, the physiological stress of fighting another illness itself acts as a reactivation trigger, creating a vicious cycle of disease.
Environmental and Demographic Determinants: The shelter data provides strong evidence for environmental factors. Poor ventilation, overcrowding, and high population turnover amplify viral shedding and transmission, but these factors also act as a source of chronic stress that promotes reactivation in latent carriers [11]. Demographically, the highest risk for primary infection and subsequent latency establishment falls on kittens and juveniles, who also tend to have higher rates of shedding upon initial stress exposure [11]. While the virus shows limited genomic variation, suggesting a stable target, its host range extends beyond domestic cats to threaten wild felids. Cases in captive snow leopards have been directly linked to FHV-1 strains originating from domestic cats, with one case strongly suspected to have died from a reactivation event [3, 8]. This highlights a critical conservation epidemiological risk, where the stress of captivity could trigger reactivation in a latent carrier, leading to fatal disease and potential transmission to naïve conspecifics [8].
Iatrogenic Factors: Vaccination as a Risk? While vaccination is the cornerstone of prevention, the epidemiology of latency is complicated by the use of modified-live virus (MLV) vaccines. Unlike inactivated vaccines, traditional MLV FHV-1 vaccines retain full virulence genes. Consequently, they can themselves establish latency in the recipient and subsequently reactivate, causing clinical disease and shedding [7]. This creates a perplexing epidemiological scenario where the tool used to control the infection can, in a subset of individuals, contribute to the pool of latent carriers and reactivation events. The development of safer, gene-deleted vaccines (e.g., TK/gI/gE deletions) that have a severely impaired capacity to establish latency and reactivate is a direct response to this epidemiological challenge [7].
In summary, the epidemiology of FHV-1 is not a static picture of infection rates, but a dynamic process governed by the host's stress and immune axis. The virus exploits periods of host vulnerability, physiological, environmental, and immunological, to reactivate, ensuring its own propagation. From the high-density shelter environment to the individual pet cat, the risk of reactivation is a constant, quantifiable factor that dictates the clinical course of this lifelong infection. The data clearly show that managing FHV-1 requires a holistic approach focused on minimizing these known risk factors to keep the latent viral genome suppressed.
Diagnostic Approaches for Detecting Latent and Reactivated FHV-1
The accurate diagnosis of feline herpesvirus type 1 (FHV-1) infection, particularly in its latent and reactivated states, represents one of the most formidable challenges in feline medicine. Unlike acute primary infections, which often present with characteristic clinical signs such as serous to mucopurulent nasal discharge, conjunctivitis, and ulcerative keratitis, latent infections are clinically silent, and reactivation episodes can be subclinical or manifest as mild, atypical, or chronic disease [1, 6]. The diagnostic armamentarium must therefore be deployed with a nuanced understanding of viral pathogenesis, the kinetics of viral shedding, and the inherent limitations of each testing modality. A comprehensive diagnostic strategy integrates molecular detection of viral nucleic acid, cytological and histopathological examination, virus isolation, and, in specific research contexts, the application of advanced imaging and immunohistochemistry. The selection of appropriate sample types, conjunctival, corneal, or oropharyngeal swabs, corneal scrapings, or tissue biopsies, is paramount, as is the timing of collection relative to the clinical episode [10].
Molecular Detection: The Cornerstone of Diagnosis
Polymerase chain reaction (PCR) has become the gold standard for detecting FHV-1 due to its exceptional sensitivity and specificity, particularly in cases of low-level shedding that may occur during latency or early reactivation [1, 2]. Real-time quantitative PCR (qPCR) offers the additional advantage of quantifying viral DNA load, which can provide critical insights into the distinction between latent carriage and active viral replication. During latency, the viral genome is maintained in a circular episomal form within sensory neurons of the trigeminal ganglia, with minimal to no transcriptional activity. Consequently, qPCR performed on trigeminal ganglia tissue from necropsy specimens can definitively confirm the establishment of latency, as demonstrated in experimental infection models where viral DNA persisted exclusively in the trigeminal ganglia during the lifelong latent phase [5]. However, the detection of FHV-1 DNA in oronasal or conjunctival swabs from a clinically normal cat does not automatically indicate active disease; it may reflect low-level, subclinical shedding from a reactivated latent infection, a phenomenon well-documented in shelter environments where stress-induced reactivation leads to a dramatic increase in shedding rates from 4% to over 50% within one week [11]. Therefore, positive PCR results must be interpreted with caution and correlated with clinical signs, as the assay cannot differentiate between viable, replicating virus and non-infectious viral DNA fragments [10].
The choice of PCR target gene significantly influences diagnostic performance. Most commercial and in-house assays target conserved regions of the viral genome, such as the thymidine kinase (TK) gene, glycoprotein B (gB) gene, or glycoprotein D (gD) gene. In a study involving the isolation of FHV-1 from snow leopards, sequence analysis of the gD and gE genes was instrumental not only in confirming infection but also in tracing the origin of the virus to domestic cats, highlighting the utility of PCR-based genotyping for epidemiological surveillance [3, 8]. For detecting reactivation, serial sampling and quantitative PCR are particularly valuable. A rising viral load over time, or the detection of viral DNA in a cat with compatible clinical signs following a known stressor (e.g., corticosteroid administration, boarding, or co-infection), provides strong circumstantial evidence of reactivation [1, 10]. The ABCD guidelines explicitly caution against sampling cats recently vaccinated with modified-live virus (MLV) vaccines, as vaccine strains can be shed and produce false-positive PCR results, complicating the distinction between vaccine-induced shedding and true infection [10].
Virus Isolation and Cytological Examination
While PCR has largely supplanted traditional virus isolation for routine clinical diagnosis, viral culture remains an important tool in research settings and for the isolation of viral strains for characterization and vaccine development. Isolation requires the collection of viable virus in appropriate transport media, followed by inoculation onto susceptible cell lines such as feline respiratory epithelial cells (FRECs) or Crandell-Rees feline kidney (CRFK) cells [4, 5]. The presence of a cytopathic effect (CPE), characterized by cell rounding, syncytia formation, and intranuclear inclusion bodies, is indicative of active viral replication. In experimental infections with the FHV-1 CH-B strain, virus was successfully isolated from nasal discharge and tissue homogenates, and the kinetics of viral replication in FRECs were meticulously characterized using virus titration and qPCR, demonstrating that intracellular virus titers were consistently higher than extracellular titers [4, 5]. However, virus isolation is time-consuming, requires specialized laboratory infrastructure, and has lower sensitivity than PCR, particularly when viral loads are low during latency or early reactivation. It is therefore not recommended as a first-line diagnostic test for latent infection but remains indispensable for phenotypic characterization of viral mutants, such as the TK/gI/gE-deleted recombinant viruses constructed via CRISPR/Cas9, where confirmation of the deletion phenotype and assessment of growth kinetics are essential [7].
Cytological examination of conjunctival or corneal scrapings can provide rapid, cost-effective evidence of FHV-1 infection, particularly in the acute phase. The characteristic finding is the presence of eosinophilic intranuclear inclusion bodies (Cowdry Type A) within epithelial cells, along with syncytial giant cells and evidence of cellular necrosis [9]. In a study of FHV-1 infection in snow leopards, histopathological examination of tissues revealed non-suppurative meningoencephalitis and interstitial pneumonia, with intranuclear inclusions identified in affected cells [3, 8]. However, the sensitivity of cytology is low, especially in chronic or reactivated disease where viral replication is limited. The absence of inclusions does not rule out FHV-1 infection, and false negatives are common. Consequently, cytology is best used as an adjunct to PCR, not as a standalone diagnostic method.
Serological Approaches: Limitations and Applications
Serological testing for FHV-1-specific antibodies (IgG and IgM) is of limited utility for diagnosing individual cases of latency or reactivation due to the high seroprevalence of the virus in the feline population. The vast majority of cats, particularly those with outdoor access or a history of upper respiratory infection, are seropositive for FHV-1 IgG, reflecting prior exposure and lifelong latency [1]. A single positive IgG titer cannot distinguish between a latent carrier and a cat experiencing active reactivation. Paired serology (acute and convalescent sera) demonstrating a four-fold rise in IgG titer may support a diagnosis of recent infection or reactivation, but this approach is impractical for clinical decision-making due to the time delay required for convalescent sampling. IgM detection is sometimes used to identify recent primary infection, but IgM responses are inconsistent and may be absent during reactivation episodes [6]. Therefore, serology is primarily reserved for epidemiological studies, vaccine efficacy trials, and population-level serosurveillance, rather than for the clinical diagnosis of latency or reactivation in individual patients.
Histopathology, Immunohistochemistry, and In Situ Hybridization
For definitive confirmation of FHV-1 latency and reactivation at the tissue level, histopathological examination combined with immunohistochemistry (IHC) or in situ hybridization (ISH) is the gold standard, particularly in post-mortem or biopsy specimens. During latency, the virus resides in the trigeminal ganglia without producing infectious virions, and conventional histology may reveal no abnormalities. However, IHC using monoclonal antibodies directed against FHV-1 glycoproteins (e.g., gB, gC, gD) can detect viral antigen within the cytoplasm or nuclei of neurons, confirming the presence of latent virus [5, 8]. In a study of experimental FHV-1 infection, viral antigen was detected in the trigeminal ganglia of cats during both the acute and latent phases, with a marked reduction in antigen-positive cells during latency [5]. ISH, which detects viral nucleic acid (DNA or RNA), offers even greater sensitivity and can differentiate between latent (DNA-positive, RNA-negative) and reactivated (DNA-positive, RNA-positive) states by targeting latency-associated transcripts (LATs) or immediate-early (IE) gene transcripts. The detection of IE gene mRNA is a hallmark of lytic reactivation, as these transcripts are absent during true latency. In the context of the snow leopard fatalities, histopathology revealed non-suppurative meningoencephalitis and interstitial pneumonia, and IHC confirmed the presence of FHV-1 antigen in affected tissues, linking viral reactivation to the cause of death [3, 8]. These techniques are invaluable for research into the molecular mechanisms of latency and reactivation, including the evaluation of novel vaccine candidates such as the TK/gI/gE-deleted mutant, where the ability to establish latency and reactivate was assessed by quantifying viral DNA loads in trigeminal ganglia post-challenge [7].
Emerging and Specialized Diagnostic Approaches
Advanced molecular and imaging techniques are expanding the diagnostic frontier for FHV-1 latency and reactivation. Droplet digital PCR (ddPCR) offers absolute quantification of viral DNA without the need for standard curves, providing superior precision for detecting low-copy-number genomes in latent tissues. This technology is particularly promising for quantifying the latent viral reservoir in trigeminal ganglia and for monitoring the efficacy of antiviral therapies aimed at reducing the latent burden. Transcriptomic analysis using RNA sequencing (RNA-seq) can identify the full repertoire of viral and host genes expressed during latency and reactivation, revealing novel biomarkers of reactivation risk. For instance, the differential expression of interferon-alpha (IFNα), tumor necrosis factor-alpha (TNFα), and interleukin-10 (IL-10) in feline respiratory epithelial cells infected with wild-type versus gene-deleted FHV-1 mutants has provided critical insights into the viral immune evasion strategies that facilitate latency establishment [4]. Furthermore, the development of recombinant FHV-1 strains expressing reporter genes (e.g., luciferase or fluorescent proteins) enables real-time, non-invasive imaging of viral reactivation in live animal models, allowing researchers to track the spatial and temporal dynamics of reactivation following stress induction. While these techniques are not yet available in clinical practice, they are driving the next generation of diagnostic and therapeutic strategies for managing FHV-1 latency and reactivation.
Immunological Mechanisms Governing FHV-1 Latency and Reactivation
The capacity of Feline herpesvirus type 1 (FHV-1) to establish lifelong latency within the host, punctuated by episodes of reactivation, is the single most consequential feature of its pathogenesis. This dynamic interplay between viral persistence and immune control defines the clinical trajectory of infected cats, transforming an acute, self-limiting respiratory infection into a chronic, recurrent condition characterized by recrudescent ocular and respiratory disease [1, 6]. Understanding the immunological mechanisms that govern this cycle is paramount to developing more effective therapeutic and prophylactic strategies. The host immune system is not merely a passive barrier to infection but an active participant in sculpting the viral life cycle, creating a fragile equilibrium that can be tipped toward either latency or reactivation by a constellation of intrinsic and extrinsic factors.
The Establishment of Immunological Sanctuary: Neuronal Latency and Immune Evasion
Following primary infection of mucosal epithelial cells in the upper respiratory tract and conjunctiva, FHV-1, like all alphaherpesviruses, exhibits a profound neurotropism. Virions gain access to the termini of sensory neurons innervating the infected mucosa and are transported via retrograde axonal transport to the neuronal soma, primarily within the trigeminal ganglia [1, 5, 6, 9]. It is within this immunologically privileged site that the virus establishes its latent state. Latency is not a state of virological dormancy in the sense of total quiescence; rather, it is an active, controlled persistence where the viral genome exists as an episome within the neuronal nucleus, with a restricted pattern of gene expression that is largely limited to the latency-associated transcripts (LATs) [5].
The establishment of latency is a direct consequence of the failure of the host immune response to completely clear the infection from this neuronal reservoir. The immune system, particularly the cell-mediated arm, plays a critical role in containing the virus during the acute phase and forcing it into latency. Studies using knockout mutants of FHV-1 have provided crucial insights into the viral genes that subvert this process. For instance, deletion of the glycoprotein E (gE) gene, which is a known virulence factor involved in immune evasion and cell-to-cell spread, alters the virus's ability to replicate and modulate the host response in feline respiratory epithelial cells [4]. Specifically, infection with a gE-deletion mutant resulted in significantly different cytokine profiles compared to wild-type virus, highlighting the active role viral gene products play in shaping the immunological landscape that precedes neuronal invasion [4].
Crucially, the virus employs sophisticated strategies to suppress the very immune mechanisms that would otherwise eliminate infected neurons. The ganglionic microenvironment during latency is characterized by a tightly regulated anti-inflammatory state. The virus itself appears to contribute to this by inducing anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). Data from in vitro studies using feline respiratory epithelial cells show that infection with wild-type FHV-1 leads to a significant increase in IL-10 and TGF-β mRNA expression, a response that is notably absent following infection with attenuated deletion mutants [4]. This suggests that the wild-type virus actively promotes an immunosuppressive cytokine milieu. While this data is from epithelial cells, it underscores a fundamental strategy: the virus orchestrates a local environment that dampens pro-inflammatory responses. In the ganglia, this translates into a checkpoint for T-cell activity. A robust, pro-inflammatory response mediated by CD8+ cytotoxic T lymphocytes (CTLs) and interferon-gamma (IFN-γ) is essential for eliminating virus-infected cells. FHV-1, however, can limit the presentation of viral antigens on the surface of infected neurons by downregulating major histocompatibility complex class I (MHC-I) molecules, a common evasion tactic among herpesviruses. Furthermore, the presence of TGF-β within the ganglionic milieu directly suppresses T-cell proliferation and effector functions, creating a "no-go" zone for effective immune surveillance. The virus also manipulates the innate immune response; wild-type FHV-1 has been shown to block the production of potent neutrophil chemoattractants like IL-8 and KC (a feline equivalent of IL-8) in epithelial cells [4]. This suppression of early innate signals, which would normally recruit effector cells to the site of infection, likely contributes to the virus’s ability to establish a foothold in the nervous system before a full adaptive response can be marshaled.
A secondary, but clinically critical, aspect of latency establishment is the metabolic state of the neuron. The arginine/lysine ratio within the cell is a known factor influencing herpesvirus replication, as the virus relies on arginine for capsid protein synthesis. The antiviral properties of L-lysine, which is often used as a dietary supplement, are thought to be based on its antagonism of arginine. In a clinical trial evaluating combination antiviral therapy, a significant decrease in the arginine-to-lysine ratio in favor of lysine was observed in successfully treated cats [2]. This suggests that manipulating host cellular metabolism can create a less permissive environment for viral replication, potentially favoring the establishment or maintenance of latency by limiting the availability of essential amino acids for viral production. This metabolic tug-of-war is a subtle but important immunological parameter in the host-virus standoff.
The Loss of Immune Control: Triggers and Mechanisms of Reactivation
Reactivation of FHV-1 from latency is not a spontaneous event but a consequence of disrupted immunological equilibrium. The virus is exquisitely sensitive to the host's physiological status, and any factor that diminishes the capacity of the immune system to maintain its tight surveillance over the latently infected ganglia can trigger a reactivation cycle. The most potent and well-documented triggers are physiological stress and exogenous immunosuppression, such as that induced by corticosteroids [1, 10, 12]. The clinical observation that shelter cats experience a dramatic increase in FHV-1 shedding, from approximately 4% upon entry to over 50% within just one week, is a stark illustration of this phenomenon, driven by the multifaceted stress of a novel environment, social disruption, and potential nutritional challenges [11]. This rapid increase is attributed to a combination of new infections and, critically, the reactivation of latent infections in stressed carriers [11].
At a molecular level, the pathway from stress to viral reactivation is complex. Stress triggers the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of glucocorticoids (e.g., cortisol). These hormones can directly transactivate the viral genome. In related alphaherpesviruses like bovine herpesvirus type 5 (BoHV-5), glucocorticoid response elements (GREs) have been identified in the viral genome, and the binding of the glucocorticoid receptor complex to these elements can initiate a cascade of viral gene expression that terminates latency [13]. While the specific GREs for FHV-1 require further characterization, the principle is highly conserved among herpesviruses. Simultaneously, glucocorticoids are profoundly immunosuppressive. They inhibit the production of pro-inflammatory cytokines like IL-1, TNF-α, and IFN-γ, and impair the function of antigen-presenting cells, CTLs, and natural killer (NK) cells. This dual action, directly stimulating viral transcription while concurrently dismantling the immune surveillance that holds the virus in check, provides a powerful and rapid route to reactivation. The stress of co-infections, such as those with feline calicivirus or bacterial pathogens, can also exert a similar immunosuppressive effect, providing the "second hit" needed for FHV-1 to escape from latency [1, 8]. This is vividly illustrated in a case report of a snow leopard where the cause of death was attributed to the concurrent reactivation of a latent FHV-1 infection, likely precipitated by stress and underlying pathology [3, 8].
Once reactivation is initiated, the virus rapidly shifts from a state of limited gene expression to a full lytic cycle. It travels via anterograde axonal transport back to the peripheral mucosal tissues, primarily the nasal passages, conjunctiva, and cornea. This return to the periphery is associated with a breakdown of the anti-inflammatory ganglionic state. The previously suppressed innate immune responses are unleashed. The data from epithelial cell studies is highly informative here: in contrast to the immunosuppressive profile seen with wild-type virus (high IL-10), infection with certain gene-deleted mutants, which are less able to establish latency, resulted in a more robust pro-inflammatory response, including a failure to block the chemoattractants IL-8 and KC [4]. This suggests that during reactivation, the virus loses its ability to maintain the suppressive IL-10/TGF-β shield, or that the massive burst of viral replication overwhelms it. The resulting immunological response at the mucosal surface is characterized by a rapid influx of neutrophils and other inflammatory cells, causing the classic clinical signs of acute FHV-1: intense neutrophilic conjunctivitis, rhinitis, and ulcerative keratitis [5, 12].
The clinical severity of reactivation events is also modulated by the adaptive immune memory of the host. In a previously infected and immunocompetent cat, reactivation is often milder and shorter than the primary infection because a memory T-cell response can rapidly expand and help control the virus at the peripheral site. However, this control is not sterilizing, and viral shedding can occur, posing an infectious risk to other susceptible animals. The virus's ability to partially re-establish this suppressive immunological state at the periphery is a key factor in the recurrent, chronic nature of FHV-1-associated ocular diseases, such as stromal keratitis and corneal sequestration, which result from repeated cycles of viral replication and immune-mediated tissue damage [1, 9]. The efficacy of antiviral drugs like famciclovir and cidofovir lies in their ability to inhibit the viral DNA polymerase during this lytic phase, thereby reducing the magnitude of the reactivation event and giving the host's immune system a better chance to reassert control without causing catastrophic tissue damage [1, 2].
The immunological control of latency is thus a delicate balance. The host’s cell-mediated immunity, particularly the CD8+ T-cell response directed against a limited set of viral antigens, is the primary force maintaining the virus in a latent state. Any perturbation that weakens this force, be it from systemic stress, pharmacological immunosuppression, or intercurrent disease, creates an opportunity for the virus to reactivate. The virus itself is an active participant, encoding gene products that help craft the local immunosuppressive environment necessary for its persistence. This complex interplay explains why stress management remains a cornerstone of clinical management for FHV-1-positive cats [1]. Vaccination, while not preventing infection or latency, primes the immune system to respond more effectively upon reactivation, reducing the severity and duration of clinical episodes [7, 10]. The ultimate goal of research, as highlighted by the development of gene-deleted vaccine candidates (e.g., TK/gI/gE mutants), is to create a stimulus that induces a robust and durable immunological memory that can more effectively police the neuronal reservoir and prevent reactivation or rapidly extinguish it with minimal collateral tissue damage [7]. FHV-1 in its natural feline host provides a powerful model for understanding the fundamental immunological principles governing alphaherpesvirus latency, principles that have direct parallels in human alphaviruses such as herpes simplex virus and varicella-zoster virus [6, 14].
Clinical Manifestations of Recurrent FHV-1 Disease Following Reactivation
The clinical recrudescence of feline herpesvirus type 1 (FHV-1) disease following reactivation from latency represents a complex and highly variable pathological spectrum, ranging from subclinical viral shedding to severe, vision-threatening ocular disease and life-threatening systemic illness. Understanding the full breadth of these manifestations is critical for clinicians managing chronically infected cats, as recurrent episodes are a hallmark of FHV-1 pathogenesis and a primary driver of morbidity in the feline population. The clinical picture is dictated by a dynamic interplay between viral factors, host immune status, environmental stressors, and the specific anatomical sites of reactivation.
The Spectrum of Recurrent Upper Respiratory Tract Disease
The most common clinical presentation of FHV-1 reactivation mirrors that of primary infection, albeit often with a less severe acute onset but a greater tendency toward chronicity. Reactivation of latent virus within the trigeminal ganglia leads to anterograde transport of virions to the mucosal epithelium of the upper respiratory tract, resulting in a resurgence of classic rhinotracheitis signs [1, 6]. Cats experiencing a reactivation episode typically present with acute-onset sneezing, serous to mucopurulent nasal discharge, and nasal congestion [2, 10]. The severity of these signs can be highly variable; some cats exhibit only mild, transient sneezing, while others develop profuse, purulent nasal discharge indicative of secondary bacterial infection, a common complication given the virus’s ability to disrupt mucosal barriers and impair local immune defenses [1, 10].
Importantly, the duration of viral shedding during reactivation is a critical epidemiological feature. While primary infection may involve shedding for up to three weeks, reactivation episodes are often characterized by a shorter, yet still infectious, period of viral excretion [10]. However, the frequency of these episodes is the primary concern. Stressors such as overcrowding, poor nutrition, concurrent illness, or the physiological stress of boarding or shelter environments are potent triggers for reactivation [1, 9, 11]. Seminal work by Pedersen et al. demonstrated the profound impact of environmental stress on FHV-1 shedding, documenting a dramatic increase from 4% of cats shedding virus upon entry to a shelter to over 50% within just one week [11]. This rapid amplification is attributed not only to new infections but, critically, to the widespread reactivation of latent infections in stressed carrier animals [11]. This phenomenon underscores the importance of stress mitigation in managing cats with a history of FHV-1, particularly in high-density housing situations.
Ocular Manifestations: The Hallmark of Recurrent Disease
Ocular disease is arguably the most clinically significant and challenging manifestation of recurrent FHV-1 infection. The virus has a pronounced tropism for ocular tissues, and reactivation frequently results in a spectrum of inflammatory conditions that can lead to permanent visual impairment [1, 6, 9]. The most pathognomonic sign of active FHV-1 ocular infection is dendritic keratitis, characterized by branching, linear ulcerations of the corneal epithelium [10]. These lesions are best visualized with fluorescein stain and a slit-lamp biomicroscope and are considered definitive evidence of active viral replication in the cornea. However, recurrent disease is not limited to this classic presentation.
Chronic conjunctivitis is an extremely common sequela of recurrent FHV-1 infection. Cats may present with persistent or waxing-and-waning conjunctival hyperemia, chemosis (conjunctival edema), and serous or mucoid ocular discharge [1, 2, 9]. This chronic inflammation can lead to significant discomfort and, over time, structural changes to the conjunctiva. A particularly debilitating complication is the formation of symblepharon, where adhesions form between the conjunctival surfaces of the eyelid and the globe, or between the nictitating membrane and the cornea [1]. These adhesions can restrict ocular motility, cause entropion (inward rolling of the eyelid), and predispose the eye to further irritation and infection.
Corneal involvement in recurrent disease extends beyond dendritic ulcers. Stromal keratitis, an immune-mediated inflammatory response within the corneal stroma, can develop, leading to corneal edema, neovascularization (ingrowth of blood vessels), and scarring [1]. This condition is particularly difficult to manage and can result in permanent corneal opacity and vision loss. Furthermore, recurrent FHV-1 infection is a primary predisposing factor for the development of corneal sequestrum, a condition where a focal area of corneal stroma undergoes necrosis, becoming a brown-to-black, opaque plaque [1, 9]. The sequestrum acts as a foreign body, causing intense pain, blepharospasm, and ocular discharge, and often requires surgical intervention (keratectomy) for resolution [1]. The pathogenesis of sequestrum is multifactorial, but chronic FHV-1-induced keratitis is considered a major inciting cause, particularly in brachycephalic breeds.
Severe and Atypical Manifestations in Immunocompromised and Non-Domestic Hosts
While most reactivation episodes in immunocompetent adult cats result in self-limiting or manageable upper respiratory and ocular signs, the clinical picture can be dramatically more severe in vulnerable populations. Young kittens, geriatric cats, and those with concurrent immunosuppressive conditions (e.g., feline leukemia virus or feline immunodeficiency virus infection) are at high risk for severe, disseminated disease [1]. In these individuals, reactivation can lead to extensive, coalescing corneal ulceration, severe necrotizing rhinitis, and pneumonia. FHV-1-induced interstitial pneumonia has been documented as a cause of death in immunocompromised cats and, notably, in non-domestic felids [3, 8].
The susceptibility of wild felids to severe FHV-1 disease following reactivation is a significant conservation concern. Case reports in captive snow leopards (Panthera uncia) have revealed that FHV-1 reactivation can precipitate fatal outcomes distinct from those typically seen in domestic cats. Wu et al. documented cases where reactivation of latent FHV-1 was implicated in the death of a snow leopard, with histopathological findings revealing not only severe upper respiratory disease but also non-suppurative meningoencephalitis and renal failure accompanied by interstitial pneumonia [3, 8]. These findings suggest that in certain felid species, or under specific physiological conditions, FHV-1 reactivation can lead to a more systemic and neurotropic disease, highlighting the unpredictable nature of the virus when host immunity is compromised or when the virus crosses species barriers. The origin of the virus in these cases was traced to domestic cats, underscoring the risk of interspecies transmission and the potential for devastating consequences in naïve or genetically susceptible wild populations [3, 8].
The Role of Secondary Infection and Chronic Inflammation
A critical aspect of the clinical manifestations of recurrent FHV-1 disease is the almost inevitable complication of secondary bacterial infections. The viral-induced necrosis and inflammation of the nasal turbinates, conjunctiva, and corneal epithelium create a permissive environment for opportunistic bacterial pathogens, most commonly Pasteurella multocida, Bordetella bronchiseptica, and various anaerobic species [1, 10]. This secondary infection transforms the character of the clinical signs, shifting from a serous to a purulent discharge and exacerbating tissue damage. In the respiratory tract, this can lead to chronic rhinosinusitis, which is notoriously difficult to resolve. In the eye, secondary bacterial keratitis can rapidly progress to corneal melting and perforation, a sight-threatening emergency [1]. Therefore, the clinical management of recurrent FHV-1 must always include vigilant monitoring for and aggressive treatment of secondary bacterial invaders.
Finally, it is essential to recognize that recurrent disease is not always clinically apparent. Subclinical reactivation, where the virus replicates and is shed in oronasal or conjunctival secretions without causing overt clinical signs, is a well-documented phenomenon [10]. These subclinically shedding cats serve as a silent reservoir of infection, perpetuating the cycle of transmission within multi-cat households, shelters, and catteries. This reality complicates diagnosis and control, as a negative clinical examination does not rule out active viral shedding. The use of sensitive molecular diagnostics like PCR is often necessary to identify these silent shedders, particularly in outbreak investigations [1, 2]. The clinical challenge, therefore, is not merely treating the overt signs of reactivation but also identifying and managing the underlying factors that precipitate these episodes, with the goal of minimizing both the clinical impact on the individual cat and the risk of transmission to others.
Therapeutic Strategies for Managing FHV-1 Latency and Preventing Reactivation
The management of feline herpesvirus type 1 (FHV-1) latency and the prevention of its reactivation represent the most formidable challenges in feline virology and clinical practice. Unlike acute infection, which is clinically overt and often self-limiting, latency is a state of perpetual biological tension: the viral genome persists within the sensory neurons of the trigeminal ganglia, transcriptionally silent yet poised for reactivation under permissive conditions [1, 6]. A therapeutic strategy that merely addresses clinical signs during active disease is fundamentally incomplete; the true objective must be to modulate the host-virus equilibrium to maintain the latent state indefinitely. This section provides an exhaustive analysis of the pharmacological, immunological, environmental, and prophylactic strategies currently available or under development for managing FHV-1 latency and preventing reactivation, drawing exclusively on the provided literature.
The Biological Context of Reactivation: A Target for Intervention
Before delineating specific therapeutic interventions, it is essential to understand the biological and epidemiological framework in which reactivation occurs. FHV-1, like all alphaherpesviruses, establishes lifelong latency following primary infection, with the viral DNA maintained as an episome in the nuclei of sensory neurons [6, 10]. Reactivation from this latent state is not a spontaneous event but is instead precipitated by specific physiological stressors. The most well-documented triggers include concurrent immunosuppressive disease, administration of corticosteroids, environmental stress (such as overcrowding, poor nutrition, or transport), and co-infections with other respiratory pathogens [1, 10, 11]. The data on shelter environments are particularly instructive. Pedersen et al. [11] demonstrated a dramatic increase in FHV-1 shedding from 4% at the time of entry to over 52% within one week in shelter populations. This rapid amplification is not solely attributable to new infections; rather, it reflects the mass reactivation of latent virus in stressed carriers, making the shelter environment a high-risk zone for both individual cats and population-level transmission. The neuropathogenic potential of FHV-1 is also a critical consideration. Although rare, reactivation in wild felids such as snow leopards has been linked to fatal outcomes, including non-suppurative meningoencephalitis and interstitial pneumonia, underscoring that reactivation is not merely a nuisance but a potentially life-threatening event in vulnerable individuals [3, 8]. Therefore, any therapeutic strategy must be assessed not only for its ability to suppress viral replication during acute episodes but also for its capacity to raise the threshold for reactivation from latency.
Pharmacological Interventions Targeting Viral Replication and Latency
The cornerstone of pharmacological management for active FHV-1 infection involves the use of nucleoside analogue antiviral drugs. Famciclovir, a prodrug of penciclovir, is the most widely recommended systemic antiviral for FHV-1 in cats. Its mechanism of action relies on viral thymidine kinase (TK)-mediated phosphorylation to its active triphosphate form, which then inhibits viral DNA polymerase [1, 2]. In a clinical trial of naturally infected cats, a combination protocol including oral famciclovir, ophthalmic acyclovir, and L-lysine resulted in an 80% reduction in clinical scores by day 10 and rendered 82.1% of cats PCR-negative for FHV-1 DNA [2]. While such results are promising for managing acute episodes, the critical question for latency management is whether these agents can suppress reactivation events. The data suggest a nuanced answer. Acyclovir and penciclovir are most effective against actively replicating virus; they do not eliminate the latent viral genome within the neuron. Therefore, their primary role in latency management is prophylactic, administered during known stress periods (e.g., boarding, surgery, or corticosteroid therapy) to reduce the magnitude of viral shedding should reactivation occur [10]. Cidofovir, a nucleoside analogue that does not require viral TK for activation, offers a theoretical advantage for treating acyclovir-resistant strains, although its use is primarily topical and limited to ocular disease [1]. Topical antivirals are invaluable for managing ocular manifestations of reactivation, such as dendritic keratitis and conjunctivitis, but they have negligible impact on the systemic latent reservoir [9]. The fundamental limitation of current antiviral therapy is that it targets active replication, not the latent state itself. No existing drug is capable of eradicating the latent FHV-1 genome, a challenge shared with other alphaherpesviruses such as varicella-zoster virus in humans [14].
Immunomodulation and Supportive Care: Raising the Host Defense Threshold
Given the inability of direct antivirals to eliminate latency, a parallel strategy focuses on enhancing the host's innate and adaptive immune surveillance to prevent reactivation. Immunomodulatory therapies, particularly interferons, have garnered significant research interest. Interferon-omega (IFN-ω) of feline origin is licensed in several countries for use in cats. The rationale is compelling: type I interferons establish an antiviral state in both infected and uninfected cells, inhibiting viral gene expression and replication. In the context of FHV-1, laboratory studies on feline respiratory epithelial cells (FRECs) have demonstrated that infection with wild-type FHV-1 suppresses the expression of interferon-alpha (IFNα) and induces immunosuppressive cytokines such as IL-10 and TGFβ [4]. This suggests that the virus actively subverts the host interferon response to favor its own persistence. Therefore, exogenous administration of IFN-ω may theoretically counteract this viral immunomodulation. While clinical evidence in naturally infected cats remains somewhat variable, the biological plausibility is strong, and interferon therapy is considered a valuable adjunct in managing recurrent FHV-1 disease [1, 9].
The role of L-lysine supplementation has been one of the most contentious topics in feline medicine. The proposed mechanism is based on the competitive antagonism between lysine and arginine; FHV-1 requires arginine for efficient replication, and excess lysine is hypothesized to reduce arginine availability, thereby inhibiting viral replication. Early studies supported this concept, but more recent evidence has been conflicting [1]. In the combination therapy study by Ozkanlar et al. [2], the arginine-to-lysine ratio did decrease significantly in favor of lysine following treatment, which correlated with clinical improvement. However, this was part of a multi-drug protocol, and the independent contribution of lysine is difficult to isolate. Current expert consensus, as reflected in the ABCD guidelines, suggests that while lysine is not harmful, its efficacy as a sole preventive agent for reactivation is not robustly supported [10]. Nevertheless, it remains a commonly used nutraceutical in clinical practice, particularly for clients seeking non-pharmacological options.
Supportive care is not merely palliative; it is a critical therapeutic intervention for preventing reactivation. The ABCD guidelines emphasize that "tender loving care" from the owner, combined with attention to nutrition, hydration, and environmental enrichment, forms the foundation of FHV-1 management [10]. This is because the most potent triggers for reactivation, stress and immunosuppression, are directly modifiable through environmental management. Anorexic cats should be offered highly palatable, warmed food. Nebulization with saline and the use of mucolytic drugs such as bromhexine can alleviate respiratory discomfort and reduce secondary bacterial infections [10]. Secondary bacterial infections are a common and serious complication of FHV-1 reactivation, exacerbating clinical signs and further stressing the host. Broad-spectrum antibiotics, such as amoxicillin-clavulanic acid as used in the combination protocol by Ozkanlar et al. [2], are therefore a rational component of therapy during active disease, though they have no direct antiviral effect.
Vaccination: Prevention of Initial Latency and Modification of Reactivation
Vaccination remains the single most important preventive strategy against FHV-1 infection and, by extension, the establishment of latency. However, it is critical to understand that currently licensed modified-live virus (MLV) and inactivated vaccines do not provide sterilizing immunity. They reduce the severity of acute disease and the magnitude of viral shedding but do not prevent infection of the trigeminal ganglia or the establishment of latency [1, 4, 6]. Indeed, commercially available MLV vaccines contain live, replication-competent FHV-1 that, while attenuated, can still establish latency and may even reactivate to cause clinical disease in vaccine recipients, raising significant safety concerns [7]. This is a fundamental limitation of current immunization strategies.
To address this shortcoming, a new generation of genetically engineered vaccines is under development. A landmark study by Yang et al. [7] constructed a recombinant FHV-1 strain with deletions in the thymidine kinase (TK), glycoprotein I (gI), and glycoprotein E (gE) genes using CRISPR/Cas9 technology. The rationale is elegant: deletion of TK renders the virus unable to replicate in non-dividing cells, including neurons, thereby severely impairing its ability to establish latency. Deletion of gI and gE, which are involved in cell-to-cell spread and immune evasion, further attenuates the virus. In experimental infections, this WH2020-ΔTK/gI/gE mutant demonstrated significantly impaired pathogenicity, high immunogenicity (inducing gB-specific antibodies, neutralizing antibodies, and IFN-β), and provided greater protection against challenge than a commercial MLV vaccine. Crucially, vaccinated cats showed significantly lower viral loads in both the lung and trigeminal ganglia post-challenge compared to controls [7]. This suggests that targeted gene deletion can not only prevent latency but also limit the size of the latent reservoir if infection does occur. Similarly, work by Lee et al. [4] using FRECs demonstrated that double-deletion mutants (gE-TK-) induced a cytokine profile more favorable to the host, including increased TGFβ expression and blocked inhibition of neutrophil chemoattractants, which may translate to enhanced immune clearance. These gene-deleted vaccine candidates represent the most promising frontier for managing FHV-1 latency at the population level. By preventing or severely restricting the establishment of latency, they address the root cause of recurrent disease rather than merely treating its symptoms.
Environmental and Population-Level Management
The management of FHV-1 latency cannot be divorced from its epidemiological context. In multi-cat environments, such as shelters, catteries, and breeding colonies, the risk of reactivation and transmission is amplified exponentially. As Pedersen et al. [11] demonstrated, the shelter environment itself is a potent reactivation trigger. Therefore, therapeutic strategies must include rigorous environmental control. This involves minimizing stress through appropriate housing density, reducing noise, providing hiding places, and ensuring consistent routines. The virus is labile in the environment and susceptible to most common disinfectants, including detergents, antiseptics, and bleach [10]. However, the latent virus within the host is untouchable by any environmental decontamination protocol. The key is to reduce the probability of reactivation events in carriers while simultaneously protecting naïve animals from exposure. This is achieved through quarantine of newly introduced animals, isolation of cats showing clinical signs, and, where feasible, testing for FHV-1 shedding using PCR during stress periods [1, 10]. In the specific context of wild felid conservation, the risk is particularly acute. Snow leopards, an endangered species, have succumbed to FHV-1 infections originating from domestic cats, with reactivation of latent virus implicated in at least one death [3, 8]. For captive wild felids, management strategies must therefore include strict biosecurity to prevent cross-species transmission, vaccination of all captive individuals with appropriate vaccines, and careful monitoring for signs of viral recrudescence, especially following stressful events such as transport or introduction to new social groups.
Future Directions and Unmet Needs
Despite significant advances, several critical gaps remain in the therapeutic armamentarium against FHV-1 latency. First, there is no approved drug that can directly target the latent viral genome, analogous to the latency-reversing agents being explored for HIV. Research on other alphaherpesviruses, such as the use of histone deacetylase inhibitors to disrupt latency in varicella-zoster virus or herpes simplex virus, has not been translated to FHV-1 [13]. Second, the role of the microbiome and systemic immune status in modulating latency is poorly understood. The finding that co-infections, such as SARS-CoV-2 triggering reactivation of latent adenovirus in humans with chronic fatigue syndrome, raises the intriguing possibility that other feline pathogens (e.g., feline calicivirus, feline leukemia virus, or feline immunodeficiency virus) may similarly influence FHV-1 latency dynamics [15]. Third, while the gene-deleted vaccines show tremendous promise, they have not yet been licensed for widespread use. The path from experimental candidate to commercial product is fraught with regulatory hurdles and manufacturing challenges. Finally, there is a pressing need for better owner education. Many owners do not understand that their cat is a lifelong carrier, even when clinically healthy, and that stress reduction is not optional but a medical necessity. The veterinary profession must therefore adopt a dual approach: advancing the science of latency disruption while simultaneously refining the art of chronic disease management through environmental stewardship and client communication.
Environmental and Stress-Related Triggers of FHV-1 Reactivation
The ability of feline herpesvirus type 1 (FHV-1) to establish lifelong latency within the sensory neurons of the trigeminal ganglia is a hallmark of its success as a pathogen. However, the clinical significance of this latent reservoir is entirely contingent upon the virus's capacity to reactivate, a process that reinitiates viral replication, anterograde transport to peripheral mucosal sites, and subsequent shedding into the environment. Reactivation is not a stochastic event; rather, it is a tightly orchestrated biological process driven by a convergence of physiological and environmental stressors that perturb the delicate host-virus equilibrium. The triggers for FHV-1 reactivation are remarkably consistent across both domestic and wild felid populations, highlighting fundamental aspects of alphaherpesvirus biology and host stress physiology [1, 6, 12]. Understanding these triggers is paramount not only for clinical management but also for comprehending viral transmission dynamics, particularly in high-density populations such as shelters and multi-cat households.
The Hypothalamic-Pituitary-Adrenal (HPA) Axis and Glucocorticoid-Mediated Immunosuppression
The single most potent and experimentally validated trigger for FHV-1 reactivation is the elevation of endogenous or exogenous glucocorticoids. This pathway, mediated by the hypothalamic-pituitary-adrenal (HPA) axis, represents the primary biological conduit through which environmental stress signals are transduced into a permissive state for viral recrudescence. The European Advisory Board on Cat Diseases (ABCD) guidelines explicitly state that stress or corticosteroid treatment can lead to virus reactivation and shedding in oronasal and conjunctival secretions [10]. This observation is not unique to FHV-1; it is a conserved feature among alphaherpesviruses, including bovine herpesvirus type 5 (BoHV-5) and human varicella-zoster virus, where stress and glucocorticoid administration are well-established reactivation triggers [13, 14].
The molecular mechanism underpinning this response is rooted in the immunosuppressive effects of glucocorticoids. These hormones, when bound to their intracellular receptors, exert pleiotropic effects on gene transcription, broadly dampening innate and adaptive immune responses. Specifically, glucocorticoids inhibit the production of key pro-inflammatory cytokines (e.g., IL-1β, TNFα) and interferons (IFN), which are critical for suppressing viral replication at the neuronal level [4]. The trigeminal ganglion, the primary site of FHV-1 latency, is not an immunologically privileged site; it maintains a constant low-level surveillance by resident immune cells. When glucocorticoid levels spike, whether from psychological stress, concurrent illness, or iatrogenic administration, this immune surveillance is compromised. The suppression of IFNα, in particular, removes a critical brake on viral gene expression, allowing the latent viral genome to initiate the lytic cascade [4]. This is why corticosteroid therapy is a well-documented precipitating factor for clinical FHV-1 disease, and why its use in FHV-1-positive cats must be approached with extreme caution.
Social and Environmental Stressors in Multi-Cat Environments: The Shelter Paradigm
While the biological pathway is defined by glucocorticoids, the proximal triggers are often social and environmental. The most compelling epidemiological evidence for stress-induced reactivation comes from studies of cats entering and residing in animal shelters. A landmark study examining viral shedding in shelter populations documented the profound impact of environment on FHV-1 dynamics. Upon entry, only 4% of healthy cats were shedding FHV-1 (likely from active primary infections or ongoing reactivation). However, after just one week in the shelter environment, the shedding rate had increased to a staggering 52% [11]. The speed and magnitude of this increase clearly indicated that the phenomenon was driven not solely by new infections from horizontal transmission, but primarily by the mass reactivation of latent virus in pre-existing carriers [11].
The shelter environment is a crucible of multiple concurrent stressors: transportation, novel surroundings, social disruption from being removed from a familiar home, high feline population density, unpredictable noise, and limited resources. Each of these factors activates the HPA axis. When these stressors are compounded by the physiological demands of a concurrent illness, the threshold for reactivation is rapidly crossed. This observation aligns with reports that latent FHV-1 reactivation can be associated with concurrent disease and physiological decline, as demonstrated in captive snow leopards where the death of one animal was directly linked to reactivation latent infection amidst other pathologies [3, 8]. The shelter data underscore a critical public health point for facility management: the mere act of sheltering a cat creates the conditions for viral amplification. Without rigorous stress-reduction protocols, the shelter itself becomes an epicenter for FHV-1 recrudescence and dissemination.
Beyond shelters, other common stressors known to precipitate reactivation include overcrowding in catteries, introduction of new animals into a household, weaning and social hierarchy disruptions, and even routine events such as boarding, travel, or veterinary visits [1, 12]. The key factor is the cat's perception of threat or lack of control, which triggers a neuroendocrine stress response potent enough to temporarily override the host's immune hold on the latent virus.
Co-Infections, Intercurrent Disease, and Immunosuppressive Therapies
A second major category of triggers involves any condition that induces a state of systemic immunosuppression or physiological crisis. Viral co-infections, such as those caused by feline calicivirus (FCV) or feline enteric coronavirus (FECV), are particularly problematic. While FCV itself is less prone to environmental spread in shelters compared to FHV, the stress of any viral infection and the associated inflammatory response can activate the HPA axis and divert immune resources, creating an opportunistic window for FHV-1 reactivation [11]. Similarly, concurrent infections with feline immunodeficiency virus (FIV) or feline leukemia virus (FeLV) induce chronic immunosuppression that dramatically lowers the threshold for FHV-1 reactivation, leading to more frequent and severe clinical episodes [1].
Intercurrent non-infectious diseases also act as potent triggers. Conditions causing chronic pain, organ failure, or metabolic derangement, such as renal failure, diabetes mellitus, or neoplasia, place a significant physiological burden on the host. The resulting systemic stress state is a well-recognized precipitant for recrudescence. In the case of the snow leopards discussed above, the primary cause of death in one animal was renal failure, which was accompanied by an FHV-1-induced interstitial pneumonia. It is highly probable that the systemic stress of the renal disease facilitated the viral reactivation [3, 8].
Iatrogenic immunosuppression, beyond corticosteroid use, is another critical consideration. Chemotherapeutic agents, and particularly drugs like cyclophosphamide that target rapidly dividing cells, can profoundly suppress lymphocyte populations and trigger reactivation. Furthermore, surgical procedures themselves, through the stress of anesthesia, tissue trauma, and the postoperative inflammatory response, are a documented risk for reactivation. This is a clinically relevant consideration for any feline patient with a known history of FHV-1 undergoing elective or emergent surgery.
Nutritional and Management Factors: The Hypolysinemia Hypothesis
The role of nutrition, specifically the balance of the amino acid arginine to lysine, has been a subject of considerable debate as a potential modulatory factor for FHV-1 replication and reactivation. The biological premise is that FHV-1, like other herpesviruses, requires high levels of arginine for viral protein synthesis. Lysine, being a structural analog of arginine, can competitively inhibit arginine transport and utilization, thereby potentially suppressing viral replication. The ABCD guidelines, reflecting an older consensus, did not endorse lysine supplementation as a primary therapy [10]. However, more recent evidence suggests that the ratio of these amino acids may be relevant when considering the metabolic state of the host during reactivation events.
A clinical study evaluating antiviral combination therapy, which included L-lysine, demonstrated that successful treatment was associated with a significant decrease in the systemic arginine-to-lysine ratio in favor of lysine [2]. This finding provides a mechanistic link between nutritional status and viral control. While lysine supplementation alone is clearly insufficient to prevent or treat FHV-1, the metabolic stress of illness often induces anorexia and catabolism, which may disrupt normal amino acid homeostasis. A cat that is anorexic due to rhinitis or conjunctivitis may have decreased lysine intake relative to arginine, potentially creating a metabolic environment more permissive for viral replication [1, 2]. Therefore, while not a direct trigger like glucocorticoids, poor nutritional intake and metabolic stress can act as a permissive co-factor that exacerbates a reactivation event initiated by other environmental or physiological stressors. This reinforces the critical importance of supportive care, including assisted feeding with highly palatable, high-quality diets, as a fundamental component of managing cats during acute FHV-1 disease and mitigating the risk of recurrence [2, 10].
The Amplification Loop: From Reactivation to Environmental Contamination
The final piece of the puzzle is the consequence of reactivation: shedding. Once reactivation is triggered, the virus is excreted in copious amounts in oral, nasal, and conjunctival secretions [10]. The cat becomes a potent source of environmental contamination. FHV-1 is a labile virus, susceptible to most common disinfectants and detergents, and it does not persist for extended periods in the environment under normal conditions [10, 12]. However, in high-density settings like shelters or catteries, the sheer volume of virus shed during a reactivation episode can saturate the local environment. This creates a transmission cascade, where newly infected cats undergoing primary infection will shed high titers of virus, and the stress of their own illness will trigger reactivation in other latent carriers [11]. This creates a positive feedback loop of infection and reactivation that is extremely difficult to break without aggressive management of both stress and disinfection protocols.
Understanding the full spectrum of FHV-1 reactivation triggers, from the molecular level of glucocorticoid signaling to the population level of shelter stressors, provides the scientific foundation for evidence-based prevention strategies. Reducing environmental stress, avoiding unnecessary corticosteroid use, managing concurrent disease, and ensuring adequate nutritional support are not merely adjunctive therapies; they are primary interventions for controlling recurrent FHV-1 disease in the individual patient and for limiting viral spread within the feline population.
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