Indian Journal of Animal Research

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Bovine Alphaherpesvirus-1 (BoHV-1) Infection in Cattle: An Overview of Epidemiology, Role of Envelope Proteins in Disease and Control


L. Rashmi1, R. Sharada1, D. Ratnamma1, S. Isloor1, B.M. Chandranaik2, H.V. Mohan3, Y.S. Roopa Devi4, S. Ranganatha1, S.S. Patil5,*
1Department of Veterinary Microbiology, Veterinary College, Karnataka Veterinary, Animal and Fisheries Sciences University, Bidar-560 024, Bengaluru, Karnataka, India.
2Institute of Animal Health and Veterinary Biologicals, Karnataka Veterinary, Animal and Fisheries Sciences University, Bidar-560 024, Bengaluru, Karnataka, India.
3Department of Veterinary Public Health, Veterinary College, Karnataka Veterinary, Animal and Fisheries Sciences University, Bidar-560 024, Bengaluru, Karnataka, India.
4Department of Veterinary Pathology, Veterinary College, Karnataka Veterinary, Animal and Fisheries Sciences University, Bidar-560 024, Bengaluru, Karnataka, India.
5ICAR-National Institute of Veterinary Epidemiology and Disease Informatics, Yelahanka-560 064, Bengaluru, Karnataka, India.

In the past decade, substantial progress has been made towards the evaluation of various antigenic proteins from Bovine alphaherpesvirus-1 (BoHV-1) that can likely be targeted for designing of a suitable control strategy. Growing knowledge on the immunology of the host systems has been highly useful in the assessment of antigenic epitopes from the virus and its receptors on the host. BoHV-1 are enveloped double stranded DNA viruses studded with a dozen (gB, gC, gD, gE, gG, gI, gH, gK, gL, gM, UL49.5 and US9) of protein molecules on their surface where, ten are glycosylated and two are non-glycosylated. Each of these proteins are known to play a role in various functions such as cell attachment, entry, viral multiplication, cell to cell movement, packaging, egress of cell, retrograde and anterograde movement of virus. Knowledge about the properties and function of envelope proteins helps to explore the right protein for in-house vaccine or diagnostic test development. Overall, the review provides a comprehensive overview of the various aspects of Bovine alphaherpes infection including the epidemiology, envelope proteins involved in enforcement of infection, vaccines and methods of detection.

Bovine alphaherpes virus-1 (BoHV-1) is a highly contagious virus that affects cattle worldwide. BoHV-1 is classified under order Herpesvirales, family Herpesviridae, subfamily Alpha herpesvirinae and genus Varicello virus. Three known subtypes of virus are BoHV-1.1, BoHV-1.2a and BoHV-1.2b (Biswas et al., 2013). BoHV-1.1 is responsible for a wide variety of clinical diseases, including conjunctivitis of one or both the eye, upper respiratory tract infection known as infectious bovine rhinotracheitis (IBR), reproductive tract lesions in cows, infectious pustular vulvovaginitis (IPV) and bulls infectious balanoposthitis (IBP) and new-born systemic infection (Jones and Chowdhury 2007; Tikoo, 1995). Latent infections and bovine respiratory disease (BRD) complex are the known sequelae of infection. Although economic loss is not well documented in India, these infections are known to lead economic downward spiral with losses up to over 3 billion dollars annually in the global livestock industry (Chen et al., 2018).
The oldest recorded case of BoHV-1 producing illness was described in Germany, in 1841 as a venereal disease in bulls and the cows that were in contact with them. This condition was described as Blaschenausschlag in German literature (Rychner et al., 1841). Reisinger and Reimann established the disease’s viral origin in 1928. Schroeder and Moy’s published the first report on respiratory IBR in 1954; they described a respiratory form of the disease in California milching cattle that was characterised by pyrexia, agalactia and respiratory symptoms. A disease that first manifested in a Colorado feedlot in 1950 and has subsequently spread throughout the state was reported in the following year by Miller (1955). Madin et al., (1956) originally isolated the etiological agent for IBR on cell culture and the initial live attenuated vaccine was produced around the same time by Kendrick et al., (1958). In India Ocular form of IBR was reported for the first time from exotic or crossbred cattle from Uttar Pradesh (Mehrotra et al., 1976), since then a substantial number of studies on seroprevalence are being  conducted in different parts of country (Nandi et al., 2011; Kollannur et al., 2014).
Virion morphology
Herpesviruses are large, enveloped, double-stranded DNA viruses. Herpesvirus core contains a linear 136 kbp, double-stranded DNA genome protected by 162 capsomers in an icosahedral symmetry (Engels et al., 1987). The diameter of nucleocapsid is 100-110 nm consisting of 150 hexamers and 12 pentamers. A tegument layer made of globular proteins separates outer envelope and the core nucleocapsid. The outer envelope is a lipid bilayer derived from host cell, contain a large number of viral encoded glycoproteins. The size of the mature virion particle varies from 120 to 300 nm in diameter (Thiry et al., 2006).
The genes on BoHV-1 is arranged as one unique long unit (UL) and one unique short unit (US) flanked by two inverted repeat sequences, referred as internal repeat  and terminal repeat (Fig 1). The UL segment has six glycoproteins, while the US segment contains four (Thiry et al., 2006). Three subtype variants of BoHV-1, designated as BoHV-1.1a, BoHV-1.2a and BoHV-1.2b, are described based on genomic DNA restriction endonuclease profiles (Metzler et al., 1985). The most prevalent BoHV subtype circulating in India is BoHV-1.1 and all isolated strains have homology  to Cooper stain (Chandranaik et al., 2010), except in one study only one subtype of BoHV-1.2 from nasal swab was isolated from the aborted animal (Saha et al., 2010). Subtype 1 virus isolates are associated with IBR and abortion and are commonly found in North America, South America and Europe. Subtype 2a in Brazil are linked to IBR, IPV IPB and abortions. Respiratory form/IPV/IPB excluding abortion are linked to subtype 2b strains found in Australia or Europe (Righi et al., 2023). Los Angeles (LA) and Cooper are the most prevalent BoHV-1 strains in United States and Europe respectively.

Fig 1: The genes on BoHV-1 is arranged as one long unique unit (UL) and one short unique unit (US) flanked by two inverted repeat sequences, named internal repeat (IR) and terminal repeat (TR).

Disease transmission and clinical signs
Direct transmission from infected animals can happen by aerosols or contact with their respiratory, ocular, or reproductive tract secretions, which aids in the spread of the disease in cattle herds. Indirect virus transmission can occur through contaminated individuals, objects, semen (Coitus or artificial insemination) and even embryo transfer (Van Engelenburg et al., 1995). Infected animals remain carriers for the remainder of their lives. When calves with latent BoHV-1 infection are exposed to natural stresses like transportation, harsh weather, overcrowding, or immunosuppressive medications (such as dexamethasone), the latent virus reactivates and spreads to hosts which are vulnerable to it (Chase et al., 2017). IBR is mainly a disease of cattle and buffaloes. Virus is also known to circulate in sheep, goat, horse, pigs, hippopotamus and mithun (Singh et al., 2017), yak and camel (Selim et al., 2022). Though mortality is less, morbidity is 100%. Anorexia, pyrexia, depression and a copious nasal discharge that is initially serous but later becomes mucopurulent are among the earliest symptoms. The nasal mucosa is hyperaemic and lesions inside the nasal cavity advance from focal necrosis with accompanying purulent inflammation to significant areas of hemorrhagic, congestion, ulcerated mucosa covered by a cream-colored diphtheritic membrane. These lesions may be difficult to see. The breath could smell foul. Deep bronchial coughs, mouth breathing, salivation and dyspnea are frequent symptoms. Acute, uncomplicated forms may last for 5-10 days.
Unilateral or bilateral conjunctivitis, along with profuse lacrimation, could be an exclusive clinical sign in cattle herd with IBR (Mehrotra et al.,1976). Gastroenteritis is prominent finding in the generalized disease of neonatal calves, also in adult cattle and could be fatal. Abortion may occur at 4 to 7 months gestation, with no much gross lesions in the foetus.  Virus has also been reported to cause mastitis or agalactia. Infectious pustular vulvovaginitis infections are associated with dairy cows. Many a times subclinical cases go unnoticed. Affected cows develop fever, depression, anorexia and stand apart, lifts the tail away from contact with the vulva; micturition is frequent and painful. The vulval labia, vestibular mucosa is reddened, swollen, with many tiny pustules and discharge. Nearby pustules coalesce to form a fibrinous pseudomembrane that covers an ulcerated mucosa (Turin et al., 2003). Uncomplicated lesions usually heal 10-14 days.
Infectious Balanoposthitis develops after 1-3 days of infection (Huck et al., 1971). Initially Penis and prepuce are reddened with coalescing pustules and discharges. Gradually adhesion, annular constriction and penile distortions may develop. In mild cases healing occurs within 10-14 days, but some animal may lose libido, have painful arousal and ejaculation and difficult to mate with female partner. BoHV-1 reduces the semen quality (Majumder et al., 2015). Recovered bull semen may be contaminated with virus because of periodic shedding. However, contaminated semen may not affect pregnancy in cattle by natural service or artificial insemination but animal in later stage develop IPV. Pregnant cows that acquire infection rarely abort. At a given point of time presence of both Genital form and respiratory form in a herd is rare event.
BoHV-1 is a successful pathogen distributed worldwide except few European countries Finland, Switzerland, Austria, Denmark, parts of Italy and Czech Republic (Iscaro et al., 2021). The incidence and prevalence of IBR are extremely variable under different geographical location and systems of rearing (Nandi et al., 2009). Prevalence of IBR is low in  Slovenia 0.1% a due to ongoing  eradication programmes (Hostnik et al., 2021) and in Spain region highest 99.92% (Dias et al., 2013). Pooled seroprevalence of IBR in China as per meta-analysis is 40.00% (Chen et al., 2018), prevalence in Colombia is 57.5% (Ortiz et al., 2022), Brazil, 71.30 (Abad et al., 2016) Mexico 76.32% (Posado et al., 2013) and Ethiopia, 25.6 (Tadeg et al., 2021).
A number of seroprevalence studies in different parts of India is given in Table 1. Prevalence is ranging from as low as 10.39% in Uttaranchal (Jain et al., 2006) to 89.00% in  Andaman and Nicobar Islands (Patil et al., 2021b). According to prevalence studies, older female cattle were reported be more susceptible than males due to the stress factors associated with parturition and substantial milk production. Many authors have described correlation between age and disease, older animals aged between 24 months to nine years of age are much more susceptible than younger animals due to maternal immunity (Palmer et al., 1990; Nyaga and McKercher, 1980). In certain studies, male animals were more susceptible than females. Disease was found to affect exotic and crossbred cattle in India during inception than native breeds. In Slovenia and Colombia HF cow breed (Hostnik et al., 2021) and in Nepal’s Jersey  breed of cattle have shown higher prevalence than other breeds (Sanjay et al., 2022). One frequent risk factor reported by many authors is herd size, where the disease was more prevalent in intensive rearing or feed lots or organised farms or farms with more than 10 animals compared to free-range animals or the unorganised sector (Rajkhowa et al., 2004). Studies have also evaluated the possibility of cross-species infections. In this regard, caprine, sheep, yak, mithun, horse, pigs, hippo and mustelid were suggested to be involved in this (Biswas et al., 2013).

Table 1: Seroprevalence of BoHV-1 in India.

Viral glycoproteins
Viral glycoproteins are key molecules that play an important role in the interactions between viruses and their host-cells. They are involved in various steps of the viral replication cycle, such as the attachment, penetration, maturation and egress of the virus. Therefore, they constitute an important target for the host immune response. Some glycoproteins have greater immunogenic properties, allowing their use as a component of vaccines and also diagnostic tests. An overview of all the Glycoproteins and their properties are listed in Table 2. The unique long segment of the genome code for six glycoproteins gB (UL27), gC (UL44), gH (UL22), gL (UL1), gK (UL53) and gM (UL10) and one non glycosylated protein UL49.5 while four genes corresponding to gG (US4), gD (US6), gI (US6), gE (US8) and a non-glycosylated protein US9 are grouped in a tandem organisation in the US segment (Barber et al., 2017). Although 6 glycoproteins (gC, gB, gD, gH, gK and gL) are involved in viral attachment and entry to host cell  four  glycoprotein ( gB, gD, gH and gL) interactions are must for a virus to gain entry. Based on deletion mutant virus construction studies  gC, gI, gE, gG and gM glycoproteins are found to be non-essential. On the contrary, gB or gD are essential for in vitro replication (Kamiyoshi et al., 2008). UL 49.5  in  Pseudorabies virus is designated  as glycoprotein N (gN) due to presence of glycosylation and known to inhibit the transporter associated with antigen processing driven peptide import into the endoplasmic reticulum.  The same UL 49.5 is non glycosylated in BoHV-1 and has the same immune evasion function. A modified diagram of BoHV-1 from Barber et al., (2017) showing all envelope proteins are depicted in Fig 2.

Table 2: Properties of BoHV-1 glycoproteins.


Fig 2: Envelope proteins of BoHV-1.

Glycoprotein D (gD)
This protein is a significant component of BoHV-1 and plays a crucial role in the fusion of the viral envelope and plasma membrane of the host cell. Along with gB and the gH-gL complex, it performs fusion process. gD has been considered as the primary vaccine candidate due to its ability to induce a robust cellular immune response and the highest neutralizing titres of antibodies against it (Dubuisson et al., 1992). Glycoprotein D can also be used to distinguish between BoHV-1 and BoHV-5, with 79.9% amino acid identity between the two (Delhon et al., 2003). Structurally gD is a type I membrane glycoprotein,  coded by US 6 gene with  a molecular weight of 71 kDa. In BoHV-1 gD, 28 amino acids of cytoplasmic tail and a hydrophobic transmembrane anchor sequence make up the carboxy-terminus and extracellular domain forms the amino terminus.
Researchers have developed various subunit and viral vector vaccines using gD that could elicit cell-mediated immune response. Subunit gD vaccines have proven to be effective in controlling spread of both BoHV-1 and BoHV-5 infections but are expensive. Recombinant gD expressed in a prokaryotic system had the ability to induce high antibody response but low virus neutralization capacity (Parker et al., 1993). Subsequently eukaryotic expression systems such as yeast, mammalian, plant and insect cells, are also tested to develop subunit vaccine incorporating adjuvants like oil based adjuvant, avridine and CpG to lower the cost (Zhu et al., 1997; Rankin et al., 2002). DNA vaccine and Viral vectored vaccine (Human adeno virus/Bovine adeno virus) encoding gD  though induce better cell mediate immune response and mucosal response  respectively needs further improvement in eliciting balanced immune response (Dummer et al., 2014). PCR targeting conserved region of gD gene (Smits et al., 2000; Wiedmann et al., 1993) and indirect ELISA based on gD recombinant protein (Ratta et al., 2020) could be used to diagnose BoHV -1 infections.
Glycoprotein B
Glycoprotein B (gB) is one of the immunodominant antigens present on the viral envelope and of plasma membrane of infected cells. This protein plays a vital role in the virus attachment to host cell, entry, cell-to-cell movement and fusion (Raaperi et al., 2012). Immunity to glycoprotein B develops rapidly after infection and lasts a long time. It also induces a strong neutralizing antibody response (Clinton and Chowdhury, 2010) and is recognized by CD4+ helper T lymphocytes (Hutchings et al., 1990). This makes glycoprotein B a potential target for subunit vaccines and diagnostics based on recombinant proteins. The glycoprotein B gene UL27 codes for a polypeptide consisting of 932 amino acids with an unusually long signal sequence, transmembrane sequence and five potential sites for the addition of N-linked oligosaccharides (Misra et al., 1988). This gene has sufficient variability to produce high-resolution phylogenetic trees and helps to classify the virus into different groups, providing more insight into its transmission and distribution (Surendra et al., 2015).
Amplification and sequencing of the gB gene by employing PCR to diagnose and also to understand the molecular epidemiology has been followed  in India as well as worldwide (Patil et al., 2006; Patil et al., 2012; Chandranaik et al., 2014; Sobhy et al., 2014; Surendra et al., 2015; Chandranaik et al., 2016).  The phylogenetic analysis of the gB gene sequences of BoHV-1 isolates by Patil et al., (2016), revealed the dominance of subtype 1.1 from India. The gB specific ELISAs are more sensitive for the detection of serum antibodies. Indirect ELISAs and gB blocking ELISAs have a highly comparable sensitivity and specificity (Beer et al., 2003).
Glycoprotein C (gC)
One of the glycoproteins involved in virus entry is glycoprotein C along with other 5 glycoproteins (gB, gD, gH, gK and gL). The gC binds to the host cell’s surface ligand, heparin sulphate, aiding in attachment to the host cell and influencing the host cell type tropism, (Liang et al., 1993; Okazaki et al., 1999). On the other hand, research on gC null mutants demonstrated that virus entrance may be independent of gC binding, though gC binding could increase the infectiousness of the virus.
BoHV-1, gC is coded by UL44 and size is 521 amino acid. It is a high immunogenic protein present on the plasma membrane of infected host cells as well as in the virus’s envelope. Both CD4 and CD8 T lymphocytes can detect it (Anonymous, 2005). It is a member of the immunoglobulin superfamily and a type I transmembrane glycoprotein (Fitzpatrick et al., 1989). There are four potential sites for addition of N linked oligosaccharide and a serine /threonine rich region (amino acid 32-92) for addition of O linked oligosaccharide. In addition the BoHV-1 gC gene has a region with strong homology to the constant domain of MHC class II antigens, but its functional significance is unknown (Fitzpatrick et al., 1989). Differences in the amino acid residue 76 between the BoHV-1.1 (valine) and BoHV-1.2 (glycine) strains helps to differentiate the two subtypes (Rijsewijk et al., 1999, Ranganath et al., 2013). A DNA vaccine expressing glycoprotein C (gC) of BoHV-1 was prepared and evaluated by Gupta et al., (2001). However it failed to induce protective immunity in bovines. In order to distinguish BoHV-1 from BoHV-5, Brower et al., (2008) targeted and sequenced the gC gene for the identification of BoHV-1 in the brain tissues of aborted foetuses (an unusual manifestation of BoHV-1). In India, gC gene amplification and phylogenetic analysis study from keratoconjunctivitis cases by Chintu Ravishankar et al., (2012) and from semen of cattle by Chandranaik et al., (2010) and buffalo Supriya et al., (2014) helped to group the isolate as a 1.1 subtype, with a 100% nucleotide sequence homology to the USA (Cooper) strain.
Glycoprotein (gE) and glycoprotein (gI) 
The open reading frame US8 gene codes for gE, which is a key factor of the virus’s virulence that has been investigated in vaccine development efforts against the virus. Although the gE is not required for viral replication, it can interact with other proteins to boost the virus’s neurovirulence and cell-to-cell transmission as well as the secondary envelope coating of its virions. The US7 gene-encoded gI forms a heterodimer with gE always and together they  participate in a variety of viral activities. The gE/gI heterodimer can also associate with the immunoglobulin G (IgG) Fc fragment, which makes it easier for the virus to evade the immune system following infection (Jones, 2007). Overall, gE exhibits most of the characteristics suitable for the development of deletion mutant vaccines.
The extracellular domain (ETD), transmembrane domain (TMD) and cytoplasmic domain (CTD) make up the structure of glycoprotein E. The formation of the gE/gI heterodimer is mainly through interaction with conserved gE ETD, which is crucial for cell-to-cell spreading and immune evasion (Ning et al., 2022). The gE/gI complex’s attachment to the IgG Fc region prevents the traditional complement pathway from being activated and shields virus-infected cells from antibody-dependent cellular phagocytosis and cytotoxicity in almost all alpha herpes viruses except bovine alphaherpes virus (Jenks et al., 2019). The interaction of gE with nearby proteins present on unique long sequences, such as UL 11, UL 16, UL 7 and UL 51, enhances cell fusion and cell-to-cell dissemination. The association of the unique short sequence protein US 9 with glycoprotein E aids in the formation of mature virions, axonal sorting and reverse axonal transport of viruses in neurons (Miranda et al., 2016).
Vaccination is the economical, safe and best method of reducing viral circulation. Traditional vaccination strategy involves use of killed or attenuated virus that elicits an immune response indistinguishable from the naturally infected animal. To overcome this problem and to eradicate the disease based on segregation of infected animals from vaccinated ones, researchers came up with new kind of vaccines called marker vaccines. Marker vaccines or DIVA strategy involves addition of novel gene or deletion of non-essential gene from the pathogen that serves as a marker to differentiate vaccinated and infected animals. This concept came up by the end of 20th century and the first licensed vaccine developed of this type was for Porcine Herpes virus (Van Oirschot et al., 1990), subsequently extended to other diseases such as  Newcastle Disease, Infectious Laryngo Tracheitis, Infectious Bursal Disease, Avian influenza, Classical Swine Fever etc (Erdem et al., 2022).
Number of gE deletion mutant vaccine constructs of alpha herpesvirus has demonstrated appreciable safety and immunogenicity, with a significant reduction in the replication and spread of the virus in the central nervous system. Examples include gE-deficient form of Equine Herpes Virus EHV-1 vaccine  equine abortion (Ning et al., 2022), gE-deficient marker vaccine prepared by replacing the gE gene with β-galactosidase, BoHV-1DgEβgal by Romera et al., (2014). In some studies along with gE other virulent genes has been considered for deletion. EGFP-labelled gE/gI-free Porcine herpes virus  (Yin et al., 2017),  gE, gI and TK triple deletion mutants of Porcine herpes virus (Hu et al., 2015) and  recombinant virus without gE/ gI/TK genes, rPRVTJ-delgE/ gI/TK-E2 in addition expressing E2 protein of classical swine fever virus (CSFV), mutants have been developed to protect against pseudorabies in pigs (Lei et al., 2016). Protection against challenge with wildtype BoHV-1 was found to be lower with Triple  (gG-/tk-/gE-) mutant vaccine compare to double mutant vaccine (gG-/tk) (Zhang et al., 2011; Marawan et al., 2021). The reason for lower protection could be  the reduced  replication efficiency of triple mutants in vivo (Kaashoek et al., 1995). Another triple gene deleted mutant vaccine (gE-/US9/UL-49.5-) administered intranasally notably cleared the challenge virus three days earlier than the BoHV-1 gE-deleted virus vaccinated group (Chowdhury et al., 2014). Both  gE- killed, gE-live vaccines are marketed  and used by European countries in IBR control programmes. Details of commercially available gE negative mutant vaccines are given in the Table 3. Inactivated gE-marker vaccines were found to be efficient in inhibiting virus secretion after reactivation (Bosch et al., 1997) and live gE- marker vaccines administered intranasally were found to induce early immune response than gE killed vaccines (Kaashoek and Van Oirschot., 1996). In addition to gE- deletion tk- deleted double mutants are known to reduce neurovirulence and latency are also presently marketed against IBR (Petrini et al., 2019). Recently, novel gene editing technology CRISPER/CAS9  has been tested to knock out gE gene and also  gE and US9 gene at the same time, proveing that the CRISPR/Cas9 system is a powerful tool for  rapidly generating mutant viruses (Liu et al., 2022).

Table 3: List of commercially available gE deleted marker vaccines against IBR.

Recombinant glycoprotein E (ectodomain/cytoplasmic domain/truncated protein) has been cloned and expressed in prokaryote, yeast cell, Baculovirus and in human embryonic kidney cells to develop ELISA, a companion test to differentiate infected and gE deletion mutant vaccinated animal (Ning et al., 2022). Indirect gE ELISA are more specific compared to gE blocking ELISA (Bertolotti et al., 2015). Glycoprotein E Milk ELISA was identified as easy and cost-effective method for surveillance programs than serum gE ELISA (Righi et al., 2022). Glycoprotein E gene amplification by PCR has also been used to differentiate infected from vaccinated animals in wild and domesticated animals (Grom et al., 2006, Wernike, 2012).
Glycoprotein (gK)
For the generation and spread of infectious viruses, BoHV-1 gK is necessary. Like Herpes Simplex Virus 1, BoHV-1 gK physically interacts with and binds with UL20 in infected cells and induces cell fusion, virus entrance and infectious virus propagation. Deletion of gK gene conducted by Muzammel et al., (2016) resulted in, failure of these viruses to form viral plaques and inability to spread infection beyond a single infected cells.
The BoHV-1 gK is coded by UL53 gene, consisting of 338 amino acids with the apparent molecular mass of 36 kDa, with four transmembrane domains, a 29 aa cleavable signal sequence and two N-glycosylation sites at asparagine positions 46 and 67, glycoprotein K is believed to be a  hydrophobic protein (Khadr et al., 1996). Conserved domains on structures of gK of other members of  alphaherpeviruses suggest, domains may serve similar functions. Amino acid sequence homologies of 46%, 44%, 53%, 43% and 46% with the gK counterparts of the herpes simplex viruses 1 and 2, equine herpesvirus 1, Marek’s disease virus and varicella zoster virus respectively, were found when the gK proteins of other members of herpesviruses were compared. Glycoprotein K deletion mutants vaccines are also promising in control of IBR (Muzammel et al., 2016).
Glycoprotein G (gG)
Glycoprotein G is Coded by US4 gene with 444amino acids and size  approximately 47kDa.  BoHV-1 gG is required for movement of virion form one cell to another in epithelial bovine kidney (MDBK) cells (Nakamichi et al., 2000) and also to maintain Cell-to-Cell Junctional Adherence among viral infected Cells (Nakamichi et al., 2002). The structure of gG is considered to be unique compared to other viral envelope proteins due to its ability to exist in different isoforms. A full-length membrane-bound form, a smaller membrane-bound form and a secreted form are three isoforms of gG. Glycoprotein G is known to interfere with the innate immune response by altering the chemokines binding, migratory directions and positioning of immune cells (Griffith et al., 2014).
Glycoprotein M (gM)
A highly conserved gM forms complex with gN in all herpesviruses via disulphide bonds. The gM/gN complex has been shown to be crucial in the packaging of different proteins during the maturation of BoHV-1 (Li et al., 2021).  Along with morphogenesis it is also involved in viral movement in cells. Only gM interacts with  tegument protein VP8 and plays a role in  translocation of VP8 to the Golgi apparatus and packaging into the virions (Sucharita et al., 2022). In gM-deleted virus (DgM BoHV-1) study, VP8 failed to move from cytoplasm to the golgi apparatus resulting in reduced VP8 concentration in mature virion. PCR targeting gM gene to study genetic variability of BoHV 1.1 showed the high similarity of genes  (98-100%) to BoHV-1.2 (Hidayati et al., 2018). Glycoprotein M is coded by UL 10 gene, with 411 aa, Mol wt 43kDa.
Glycoprotein H (gH)
Essential for infectious entry and spread from cell-to-cell of BoHV-1 (Christina and Gunther, 1999). Glycoprotein H is one of the highly conserved glycoproteins among envelope proteins of herpesviruses, coded by UL 22 gene, with 842 aa having molecular weight of 88.3kDa.
Glycoprotein L (gL)
Glycoprotein L is a 17 kDa protein, comprising of 156 amino acids. It is coded by UL 1 gene. It is a conserved glycoprotein helps in folding of gH, entry as well as transport of virus (Jones, 2019).
BoHV-1 non glycosylated protein UL49.5 is named as glycoprotein N (gN), in other members of alphaherpes viruses. UL 49.5 downregulates host CMI response by proteolytic degradation of the TAP complex, (Koppers et al., 2005) which is known to block the  transporter-associated antigen processing (TAP)-mediated transport of cytosolic peptides into the endoplasmic reticulum affecting the endocytic pathway of antigen  processing. Peptide transport by TAP is pre-requisite for loading of antigen on to MHC class I and activation of CD8+ T cells. Experimental Infection of calves with a UL49.5 free BoHV-1 mutant lead to enhanced virus neutralizing antibody and cellular immune responses when compared to the parental wild-type virus (Jones, 2019).
Interaction of US9 with other nearby envelope proteins such as gE and gI helps in axonal anterograde transit of viruses in neurons, axonal sorting and formation of mature virions (Butchi et al., 2007, DuRaine and Johnson, 2021). US9 belong to type II membrane polypeptide with no extracellular domain. Cytoplasmic domains of gE, gI and US9 are loaded with the intracellular sorting motifs (di-leucine, tyrosine motifs and acidic and basic clusters) of gE, gI and US9 play vital roles in movement of  the proteins to sites of virus assembly and then beyond to the cell surface and into axons (Tirabassi and Enquist, 2000). Deletion mutant study specific to cytoplasmic domain of US9 aminoacid 83 to 90 has resulted in inhibition of reactivation of virus in the trigeminal ganglion and anterograde axonal transport from trigeminal ganglion to nose and eye (Chowdhury et al., 2011).
Diagnosis and control
Virus culture on MDBK cell lines, Immune peroxidase or Immune florescent test are the direct methods of detecting virus. Virus infected MDBK cell line shows syncytia, grape like clustering and characteristic eosinophilic intranuclear inclusion bodies. Virus nucleic acid detection can be performed by targeting specific genes of BoHV-1 gB, gE, gC or gD genes by PCR technique (OIE, 2018). The serological tests used for the detection of IBR viral antibodies are Serum Neutralization, Indirect Enzyme Linked Immunosorbent Assay, Monoclonal antibody-based blocking ELISA, indirect haemagglutination test, dot enzyme linked immunosorbent assay, fluorescent antibody technique, complement fixation test, agar gel immunodiffusion test and counter immunoelectrophoresis etc. (Chatterjee et al., 2016). Detection of Antibodies in milk or serum by ELISA are regularly conducted in surveillance programmes (Righi et al., 2022). 
Control measures includes following strict hygienic measures at the farm premises, Vaccinating the animals at the right time, detection and removal of infected animals, Quarantine for the period of 4 weeks before introducing new animal to the herd, avoiding natural mating, artificial insemination using semen from BoHV-1 negative bulls and restriction on import of animal semen or embryo.
BoHV-1 is an important pathogen that affects milk yield, body condition and birth of young ones incurring financial loss to farmers. Except in some parts of European countries virus is reported from throughout the world. Government of India has implemented only screening of semen samples for BoHV-1 in breeding mother bulls but various epidemiological studies carried out in India indicate the need of implementation of vaccination policy and eradication programmes. Among dozens of envelope proteins exploring right glycoproteins is important in developing cost effective, in-house vaccines or diagnostic tools. Glycoprotein D is significantly immunogenic and subunit vaccine candidate confer protection against BoVH-1 and also BoVH-5. Glycoprotein C gene analysis by polymerase chain reaction helps to differentiate BoVH-1.1 and BoVH-1.2. A gE- live or killed marker vaccine has proven to be promising in inducing protective immune response and in such animals gE companion ELISA  are used to differentiate infected animals from vaccinated. Analysis of genes of gB/ gC/ gD and gE by PCR or use of expressed and purified proteins in ELISA plays an important role in diagnosis and cost effective epidemiological studies. The gene US9 deletion inhibits the reactivation of virus in the trigeminal ganglion and anterograde axonal transport. This could be exploited with tk and gE deletion mutants to resolve the problems associated with latent infections. Further, novel CRISPER/CAS9 targeted gene editing system could be employed to produce deletion mutants and also as an antiviral tool to cure infected cells. 
The authors declare that they have no conflict of interest.

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