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1-1-2008
A Review of the Biology of Bovine Herpesvirus
Type 1 (BHV-I), Its Role as a Cofactor in the
Bovine Respiratory Disease Complex and
Development of Improved Vaccines
Clinton J. Jones
University of Nebraska - Lincoln, [email protected]
Shafiqul Chowdhury
Kansas State University, Manhattan, KS
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Jones, Clinton J. and Chowdhury, Shafiqul, "A Review of the Biology of Bovine Herpesvirus Type 1 (BHV-I), Its Role as a Cofactor in
the Bovine Respiratory Disease Complex and Development of Improved Vaccines" (2008). Papers in Veterinary and Biomedical Science.
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OCambridge University Press 2008
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ISSN 1466-2523
Animal Health Research Reviews 8i2); 187-205
DOI: 10.101 7/S146625230700134X
A review of the biology of bovine herpesvirus
type 1 (BHV-I), its role as a cofactor in
the bovine respiratory disease complex
and development of improved vaccines
Clinton ]ones1t2*and Shafiqul chowdhury3
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,
'Department of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, Fair Street
at East Campus Loop, Lincoln, NE 68583-0905, USA
2~ebraska
Center for Virology, University of Nebraska, Lincoln, Fair Street at East Campus Loop,
Lincoln, NE 68583-0905, USA and
3~epartmentof Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State
University, Manhattan, KS 66506, USA
Received 14 August 2007; Accepted 12 October 2007
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Abstract
Infection of cattle by bovine herpesvirus type 1 (BHV-1) can lead to upper respiratory tract
disorders, conjunctivitis, genital disorders and immune suppression. BHV-1-induced immune
suppression initiates bovine respiratory disease complex (BRDC), which costs the US cattle
industry approximately 3 billion dollars annually. BHV-1 encodes at least three proteins that
can inhibit specific arms of the irnmune system: (i) hICPO inhibits interferon-dependent
transcription, (ii) the UL41.5 protein inhibits C D ~ ' T-cell recognition of infected cells by
preventing trafficking of viral peptides to the surface of the cells and (iii) glycoprotein G is a
chemokine-binding protein that prevents homing of lymphocytes to sights of infection.
Following acute infection of calves, BHV-1 can also infect and induce high levels of apoptosis
of CD4' T-cells. Consequently, the ability of BHV-1 to impair the immune response can lead to
BRDC. Following acute infection, RHV-1 establishes latency in sensory neurons of trigeminal
ganglia (TG) and germinal centers of pharyngeal tonsil. Periodically BHV-1 reactivates from
latency, v i n ~ sis shed, and consequently virus trans~nissionoccurs. Two viral genes, the latency
related gene and ORF-E are abundantly expressed during latency, suggesting that they regulate
the latency-reactivation cycle. The ability of BHV-1 to enter permissive cells, infect sensory
neurons and promote virus spread from sensoxy neurons to rnucosal surfaces following
reactivation from latency is also regulated by severz~lviral glycoproteins. The focus of this
review is to sun~marizethe biology of BHV-1 and how this relates to BRDC.
Keywords: bovine herpesvin~stype 1 (BHV-I), bovine respiratory disease complex (BIIDC),
pneumonia, immune suppression, latency, pathogenesis
Disease and clinical symptoms induced by bovine
herpesvirus type 1 (BHV-1)
BHV-1 is an a-herpesvirin'le subfamily mernber that
Causes significant economical losses to the cattle industry
(Turin et al., 1999). Three BIIV-1 subtypes, BHV-1 1 (11,
BHV-1.2a (2a) and BHV-1.2b (Zb), have been ~clentlfied
2
'Corresponding author. E-mall: [email protected]
based on antigenic and genomic analysis (Metzler et nl.,
1985). Subtype 1 v i n ~ sisolates are the causative agents of
infectioits boxrine rhinotracl~eitis(IBR) and are Freq~lently
found in the respiratory tract as well as aborted fetuses.
Subtype 1 strains are prevalent in Europe, North America
and South America. Subtype 2a is frequently associated
with a broad range of clinical manifestations in the
respiratory and genital tracts such as IBR, infectious
pustular vl~lvovaginitis(IPV), balanopostitis (IPB) and
abortions (Oirschot, 1995). Subtype 2a is prevalent in
C . Jones and S. Chowdhury
Brazil and was present in Europe prior to the 1970s
(Oirschot, 1995). Subtype 2b strains are associated with
respiratory disease and IPV/IPB, but not abortion
(Oirschot, 1995; D'Arce et al., 2002). Subtype 2b strains
are less pathogenic than subtype 1 and are frequently
isolated in Australia or Europe, but not Brazil (Edwards
et al., 1990).
In feedlot cattle, the respiratory form of BHV-1 is the
most common (subtype 1 strains). In breeding cattle,
abortions or genital infections tend to be more common.
Genital infections can occur in bulls (IPB) and cows (IPV)
within 1-3 days of mating or close contact with an
infected animal. Transmission can also occur in the
absence of visible lesions and through artificial insemination with semen from sub-clinically infected bulls.
The incubation period for the respiratory and genital
forms of BHV-1 is 2-6 days (Yates, 1982). With respect to
respiratory disease, clinical symptoms include high fever,
anorexia, coughing, excessive salivation, nasal discharge,
conjunctivitis with lacrimal discharge, inflamed nares, and
dyspneae if the larynx becomes occluded with purulent
material. Nasal lesions consist of numerous clusters of
grayish necrotic foci on the mucous membrane of septa1
mucosa. In the absence of bacterial pneumonia, recovery
typically occurs 4-5 days after the onset of clinical
symptoms. Abortions can occur at the same time as
respiratory disease, but may also be seen up to 100 days
after infection, which is likely due to reactivation from
latency.
With respect to genital infections, the first clinical signs
are frequent urination and a mild vaginal infection (Yates,
1982). It is also common to observe swollen vulva or
small papules followed by erosions and ulcers on the
mucosal surface. In bulls, similar lesions occur on the
penis and prepuce. If secondary bacterial infections
occur, there may be inflammation of the uterus and
transient infertility with purulent vaginal discharge for
several weeks. In the absence of bacterial infections,
animals usually recover within 2 weeks after infection.
Regardless of the involvement of secondary bacterial
infection, BHV-1 establishes lifelong latency following
acute infection.
The seroprevelance of BHV-1 ranges from 14 to 60% in
Africa and from 36 to 48% in Central and South America
(Straub, 1990). In The Netherlands, 49% of cows that give
birth to their first calf are seropositive, whereas 91% of
older cows are seropositive (Wuyckhuise et al., 1994).
Serological testing and removal of infected animals
has been successfully used to eliminate BHV-1 from
Denmark, Switzerland and Austria (Ackermann and
Engels, 2005). In these countries, cattle populations are
relatively small and movement of cattle can be controlled.
With respect to the United States and other countries,
eradication would be difficult, perhaps impossible, and
very expensive.
The seroprevalence of BHV-1 in bison raised on a
ranch is 43.8% (Sausker and Dyer, 2002), indicating that
infection can readily occur in bison. One would assume
that BW-1 is readily transmitted from buffalo to cattle
and vice versa. Since more buffalo meat is being
consumed each year in the United States, BHV-1
infections will have an impact on the emerging bison
industry. It is not clear what the percentage of seropositive animals is due to vaccination. Nevertheless, it is
clear that BHV-1 is widely disseminated in the field.
Relationship between BHV-1-induced immune
suppression and bovine respiratory disease
Bovine respiratory disease complex (BRDC), also referred
to as 'shipping fever', costs the US cattle industry at
least $3 billion
(Tikoo et al., 1995a, b; National
Agricultural Statistics Service (NASS), 1996; Bowland and
Shewen, 2000). In addition to the clinical symptoms
described above for BHV-1, BHV-1 can initiate BRDC by
transiently suppressing the immune system of infected
cattle (Yates, 1982). BHV-I-induced immune suppression
leads to secondary bacterial infections (Pasteurella
haemolytica, Pasteurella multocida and Haemophilus
somnus for example) that can cause pneumonia (Yates,
1982). Increased susceptibility to secondary infection
correlates with depressed cell-mediated immunity after
BHV-1 infection (Griebel et al., 1987a, b, 1990; Carter
et al., 1989). c D ~ ' T-cell recognition of infected cells
is impaired by repressing expression of major histocompatibility complex (MHC) class I and the transporter
associated with antigen presentation (Hariharan et al.,
1993; Nataraj et al., 1997; Hinkley et al., 1998). CD4' T-cell
function is impaired during acute infection of calves
because BHV-1 infects CD4' T-cells and induces apoptosis (Winkler et al., 1999). Two viral genes, bICPO and
UL41.5, can inhibit specific immune responses in the
absence of other viral genes. A discussion of these genes
and how they inhibit immune responses is provided
below.
The blCPO protein activates viral gene expression
and inhibits interferon (IFN) signaling pathway
The bICPO protein is the major transcriptional regulatory
protein because it activates expression of all viral promoters (Everett, 20001, and the bICPO transcript is
constitutively expressed during productive infection
(Fraefel et al., 1994). The ICPO homologues encoded by
BHV-I and herpes simplex virus type 1 (HSV-1) contain a
well-conserved C3HC4 zinc RING finger near their
respective N-termini (Fig. 1A). Mutational analysis has
demonstrated the importance of the C3HC4 zinc RING
finger domain of bICPO and ICPO (Everett, 1987, 1988;
Everett et al., 1993; Inman et al., 2001~).ICPO (Maul et al.,
1993; Maul and Everett, 1994; Everett et al., 1997, 1999a,
b) and bICPO (Parkinson and Everett, 2000; Inman
A review of the biology of bovine
189
herpesvirus type 1 (BHV-1)
f7jssrq
NLS
\
TAD
\
\
.-.
Acidic
,domain
\
\
\
(B)
LR-RNA
\
'
Latent
\
Lytic
TAD Zinc RING
finger
--I
4-
4.
0
7.
w
-b
r
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Reading frame A
LR-ORF
Reading frame B
8
kflow-2 k r , ) a * * * l w* ]
Reading frame C
(25
-
RF-C (30 kDf
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Fig. 1. Schematic of blCPO, LR gene and ORF-E genes within the BHV-1 genome. (A) schematic of BHV-1 genome, location of
blCPO and ORF-E. Domains within blCPO include an NLS (nuclear localization sequence), TAD (transcriptional activation
domain), acidic domain and the C3HC4zinc RING finger. (B)The start sites for LR-RNA transcription during latency and
productive infection were previously described (Devireddy and Jones, 1998; Hossain eta/., 1995).The C-termini of blCPO and
ORF-E overlap the LR gene and are antisense with respect to blCPO and ORF-E. Reading frames B and C (RF-B and RF-C) each
contain an open reading frame (ORF)that lacks an initiating Met. The (*) denotes the position of stop codons that are in frame
with the respective ORF.
et al., 2001~)colocalize with and disrupt the protooncogene promyelocytic leukemia protein-containing
nuclear domains. Disruption of the bICPO zinc RING
finger prevents trans-activation of a simple viral promoter
(Zhang and Jones, 2005) and impairs the ability of bICPO
to stimulate plaque formation following transfection
of BHV-1 DNA into cultured bovine cells (Inman et al.,
2001c; Geiser and Jones, 2003). The bICPO protein
contains two transcriptional activation domains (TAD)
and a nuclear localization signal (NLS) that is necessary
for efficient transcriptional activation (Zhang and
Jones, 2005) (Fig. 1A). Unlike most transcription factors,
bICPO or ICPO does not apparently bind to specific
DNA sequences, suggesting that bICPO activates transcription by interacting with cellular transcriptional
machinery. Support for this prediction comes from
the finding that bICPO associates with chromatin remodeling enzymes, histone deacetylase 1 (HDACI)
(Zhang, 2001) and p300, a histone acetyl transferase
(Zhang and Jones, 2001). The ability of bICPO to associate
with HDACl and p300 correlates with activating viral
transcription.
In the absence of other viral genes, blCPO inhibits IFN
signaling (Henderson et al., 2005). bICPO (directly or
indirectly) reduces IRF3 (IFN regulatory factor 3) protein
levels in human or bovine cells, which consequently leads
to reduced IFN-P promoter activity (Saira et al., 2007).
In addition, bICPO inhibits the ability of IRF7 to activate
IFN-P promoter activity, but bICPO does not dramatically
reduce IRF7 protein levels (Saira et al., 2007). The RING
finger of ICPO (Van Sant et al., 2001; Boutell et al., 2002;
Boutell and Everett, 2003) and bICPO (Dia et al., 2005) is
an E3 ubiquitin ligase, suggesting that the bICPO RING
finger mediates IRF3 degradation. The finding that a
functional proteasome is necessary for bICPO-induced
IRF3 degradation (Saira et al., 2007) supports the notion
that the bICPO RING finger mediates IRF3 degradation.
The RING finger is not the sole component necessary
for bICPO-induced IRF3 degradation because specific
mutations near the C-terminus of bICPO are also important
(Saira et al., 2007). Additional studies are necessary to
understand how bICPO inhibits IRF7 induction of IFN-P
promoter activity as well as the mechanism by which
bICPO induces IRF3 degradation.
What role does IRF3 play during IFN production, and
why is it important for bICPO to target IRF3 functions?
Following virus infection, two cellular protein kinases,
IKK-E or TBK-1, phosphorylate serine residues at the
C-terminus of IRF3, which induces IRF3 homodimerization and nuclear translocation (Fitzgerald et al., 2003;
Sharma et al., 2003). Nuclear IRF3 associates with other
transcriptional activators resulting in direct binding
and stimulation of IFN-P promoter activity (Wathelet
et al., 1998). IRF3 also directly binds several consensus
DNA-binding sites, including ISRE (IFN response
elements), and can consequently stimulate transcription
of IFN-stimulated genes in the absence of IFN (Guo et al.,
2000; Mossman et al., 2001). IRF3 activation is an
immediate early regulator of the IFN response, whereas
IRF7 is believed to be a component of the early response
(Yoneyama et al., 1998; Yuang et a[., 1998; Sato et a/.,
2001). Surprisingly, IRF7 is more important with respect to
C. Jonesand S. Chowdhury
190
10
20
M PRSPLIVAVVAAALFAIVRGR
3
0
Fig. 2. Schematic of the BHV-1 gN protein. Predicted amino acid sequences of the BHV-1 gN (UL49.5) protein (120).
Predicted signal sequence amino-terminal 22 amino acids (shaded letters), luminal domain (dashed line) and transrnembrane
domain (underlined) are indicated. Conserved cysteine residue (C42) within the luminal domain and a cysteine residue within
the transmembrane domain are boxed.
inhib~tingviral infection when IRF3 versus IKF7 knockout
mice are compared (Honda et al., 2005). Since BHV-1
does not grow in mice unless they lack IFN receptors
(Abril et al., 2004), it is clear that the ability of BHV-1 to
inhibit innate immune responses, IFN for example, is
cnicial for pathogenesis in cattle and host range.
The BHV-1 UL49.5 open reading frame (ORF), also
known as glycoprotein N (gN), encodes a 96-amino-acid
protein with an apparent molecular mass of 9 kDa (Liang
et al., 1993). The UL49.5 ORF contains a signal peptide
(N-terminal 22 amino acids), an extracellular domain of
32 amino acids, a transmembrane region of 25 amino
acids and a 17 amino acids long cytoplasmic tail (Liang
et al., 1993) (Fig. 2). The LJL49.5 protein is expressed as a
non-glycosylated type I membrane protein (Liang et al.,
1993, 1996).
All gN herpesvirus orthologues studied to date form
complexes with glycoprotein M (gM), which is encoded
by the ULlO ORF Uons et al., 1998; Wu' et al., 1998;
Rudolph et al., 2002). gM is important for secondary
envelopment because in PRV secondary envelopment in
the Golgi and subsequent egress require gM, in the
absence of gE (Brack et al., 1999). The gN ho~nologues
encoded by PRV and BHV-1 inhibit transporter-associated
antigen processing (TAP)-mediated transport of cytosolic
peptides into ER, which consequently blocks the
assembly of peptide-containing ternary MHC-I complexes
in vitm in virus-infected cells (Koppers-Lalic et al., 2005;
Lipiriska et al., 2006). Furthermore, the BHV-1 gN targets
the TAP complex for proteosomal degradation (KoppersLalic et al., 2005). The TAP complex consists of a
TAPl/TAP2 heterodimer, both of which are members
of the ATP-binding cassette transporter superfamily
(Androlewicz et al., 1993; van Endert et al., 2002; Koch
et al., 2004).
Peptide transport by TAP is a critical step in MHC class I
antigen presentation (Ahn et al., 1996; Hughes et al., 1997;
Ambagala et al., 2004; Koppers-Lalic et al., 2005). In the
absence of a functional TAP transporter, most MHC class I
molecules are not loaded with peptides (Hughes et al.,
1997). However, they are retained within the ER and
ultimately directed for degradation by the proteasome
(Hughes et al., 1997). Structurally, both gM and TAPS are
similar because they both contain multiple membrane
spanning segments (Wu et al., 1998; Koch et al., 2004). A
gN mutant that lacks the cytoplasmic tail can still I~indto
the TAIJ complex and Idock peptide transport, but this
mutant gN protein does not degrade TAP (Koppers-Lalic
et ul., 2005). However, when the transme~nbranedomain
in addition to the cytoplasn~ictail is truncated, gN no
longer blocks TAP function (Koppers-Lalic et al., 2005).
Therefore, sequences within the g N transmeml>rane
domain are likely to interact with TAP. The phenotype
of a viral strain expressing the various gN mutant proteins
has not been tested in the context of a virus and/or virally
infected cells. In summary, the ability of gN to inhibit TAP
is hypothesized to prevent virus-infected cells from being
killed by CD8' T-cells.
Viral encoded structural proteins mediate cell entry
and pathogenesis
To fully understand the role that BHV-1 plays in BRDC,
one must understand how BHV-1 initiates productive
infection. Consequently, this section summarizes what we
know about how the virus enters cultured cells and
disseminates in uiuo.
a-Herpesvirus glycoproteins are required for viral
particles to bind and penetrate permissive cells. In
addition, a subset of viral glycoproteins is necessary for
virus release, cell fusion and cell-to-cell spread. Ten of the
12 BHV-1 envelope proteins (gB, gC, gD, gE, gG, gH, g1,
gL, gM and gK) are glycosylated and two (gN and Us9) are
non-glycosylated (Van Drunen Littel-van den Hurk and
Babiuk, 1986; Liang et al., 1993; Baranowski et al., 1995,
1996; Khattar et al., 1996; Schwyzer and Ackermann,
1996; Brideau et al., 1998; Meyer etal., 1998; Mettenleiter,
2000, 2002; Konig et al., 2002; Nakamichi et al., 2002;
Chowdhury et al., 2006). Five envelope proteins (gB, gD,
gH, gL and gK) are essential for growth in cultured cells,
whereas the remaining seven (gC, gE, gG, gI, gM, gN
and Us9) are not essential for growth in cultured cells
(Schwyzer and Ackermann, 1996; Brideau et al., 1998;
Butchi et al., 2007).
All a-herpesvirus gC homologues (including BHV-1)
facilitate attachment of virus particles to the cell surface
by binding to heparan sulfate proteoglycan (Okazaki
et al., 1991). In the absence of gC, gB complements the
attachment function of gC by binding to heparan sulfate
A review of the biology of bovine herpesvirus type 1 (BHV-1)
(Li et al., 1995; Mettenleiter, 2002). Following initial
attachment mediated by gB and/or gC, the next step in
viral entry requires the interaction of gD with the cellular
receptor nectin 1, also known as HveC (Spear, 1993,
2004; Campadelli-Fiume et al., 2000, 2007; Spears et al.,
2000; Mettenleiter, 2002; Spear and Longnecker, 2003;
Campadelli-Fiume and Gianni, 20061, o r HVEM, a
member of the tumor necrosis factor family of proteins
(Montgomery et al., 1996). Kectin 1 belongs to a family of
intercellular adhesion molecules whose ectodomain
contains three immunoglobulin-like domains (Ogita and
Takai, 2006). Certain members of the tumor necrosis
factor family can induce apoptosis (Schmitz et al., 20001,
suggesting that an interaction between gD and HVEM
induces apoptosis in certain cell types (Hanon et al.,
1998). Following gD-receptor binding, gB and/or a gH-gL
complex interacts with cellular membrane protein(s1
leading to fusion of the viral envelope to the cell
membrane (Pertel et al., 2001; Mettenleiter, 2002; Spear
et al., 2006; Campadelli-Fiume et al., 2007; Reske et al.,
2007). The mechanism of viral and cellular membrane
fusion is not well understood other than the fact that
gD-receptor binding must occur prior to the fusion
process (Mettenleiter, 2002; Spear et al., 2006). Viral entry
into an adjacent cell (cell-to-cell spread) also requires gD
because gD-deleted viruses are incapable of cell-to-cell
spread (Fehler et al., 1992). In stably transformed cells
expressing gD, cell-to-cell spread of wild-type (wt) virus
is restricted (Dasika and Letchworth, 19991, suggesting
that gD binds to putative cellular receptors, which are
present on the apical cell membrane at the cell surface
and lateral cell membrane located at intercellular junctions (Dasika and Letchworth, 1999; Carnpadelli-Fiume
et al., 2000, 2007; Sakisaka et al., 2001; Campadelli-Fiume
and Gianni, 2006). Although g1) is an essential glycoprotein for v i n ~ sentry into the cell, a compensatory
mutation in gH at amino acid residue 450 (mutation of
glycjne to tryptophan) mediates gD-independent entry
and cell-to-cell spread of a g1)-cleleted virus (Schroder
et al., 1997).
Interactions between gE and gI also promote cellto-cell virus spread, and gE and/or gI deletion mutants arc
defective in cell-to-cell spread (Dingwell and Johnson,
1998; Cho~vdhuryet al., 1999; Mettenleiter, 2000, 2002).
Based on results from HSV-1 studies, it appears that gE
binds to a putative cellular receptor located at cellular
junctions (Dingwell and Johnson, 1998). Of the nonessential envelope proteins, gE has received a lot of
attention because it is required for anterograde neuronal
spread in oirjo and neurovinrlence (Enquist et nl., 1999).
gE-deleted viruses are transported retrograclely from the
nose and eye via the maxillary anti ophthalmic bmnch of
trigeminal ganglia (TG) where they establish latency in
sensory neurons (Enquist et al., 1999; Chowdhury et al.,
2000; Liu et al., 2007). gE-deleted viruses do not reactivate
from latency because they cannot spread in an
anterograde direction from sensory neurons in TG to
non-neuronal cells in the nose or ocular cavity (Enquist
et al., 1999; Liu et al., 2007).
The envelope protein (Us9) is also important for
anterograde neuronal spread because calves latently
infected with Us9-deleted viruses d o not shed virus
in the nose and eye following dexamethasoneinduced reactivation (Butchi et al., 2007). Interestingly,
Us9-deleted BHV-1 and pseudorabies virus (PRV) d o not
have a phenotype following infection of epithelial cells in
culture (S. I. Chowdhury, unpublished data). With respect
to PRV, the Us9-deleted virus has a defective anterograde
neuronal spread phenotype because in the absence
of Us9, axonal transport of viral glycoproteins or
vesicles containing viral glycoproteins does not occur
(Tomishama and Enquist, 2001). Therefore, the Us9
function is neuron-specific and is required only in the
context of anterograde neuronal transport.
BHV-1 gG is secreted after proteolytic processing. In
addition, gG is present o n the virus envelope and is
associated with infected cell membranes (Bryant et al.,
2003). Like other a-herpesvirus gG homologues, the
BHV-1 gG has chemokine binding activity because it
blocks the interaction of chemokines with cellular
receptors and glycol-aminoglycans (GAGS). The chemokine binding activity of gG also occurs o n cell membranes
because membrane-anchored forms of gG bind to various
chemokines (Bryant et al., 2003). Deletion of the
BHV-1 gene encoding gG leads to viral attenuation in
calves because the mutant virus is more immunogenic
(Kaashoek et a/., 1996b). The chemokine binding activity
encoded by BHV-1 gG is responsible for the attenuated
phenotype following infection of calves (Bryant et al.,
2003). In summary, these studies indicate that numerous
viral genes are necessary for initiating productive
infection and cell-to-cell spread.
The BHV-1 latency-reactivation cycle of BHV-1
Acute infection leads to high levels of virus
production
In the field, it is recognized that BRDC is not always
associated with acute BFIV-1 infection. It is generally
believed that the ability of BHV-1 to reactivate from a
latent infection can initiate BRDC. The goal of this section
is to summarize our current knowledge of the BHV-1
latency-reactivation cycle.
Acute BHV-1 infection is initiated on nlucosal surFdces
and resirlts in high levels of programmed cell death
(Wlnkler et al., 1999). Infection of permissive cells
(Devireddy and Jones, 1999) with BHV-1 also leads to
rapid cell death, in part, due to apoptosis. Viral gene
expression is temporally regulated in three distinct
phases: immediate early (IE), early (El or late (L). IE
gene expression is sti~nulatedby a virion component,
a-TIF (Misra et nl., 1995). Two IE transcription units exist:
C. Jonesand S. Chowdhury
192
Acute infection
(High levels of infectious virus)
Establishment of latency
Neuronal death?
LR gene inhibits apoptosis
LR gene inhibits productive infection
OW-E enhances neuronal 'health'
Neuronal factors also inhibit productive infection
CMI response in TG
v
Maintenance of latency
LR gene expression
LR gene inhibits apoptosis
LR gene inhibits bICPORNA expression
ORF-E enhances neuronal 'health'
Reactivation from latency
Reduced LR and ORF-E gene expression
Increased viral gene expression--> infectious virus
Stress (increased corticosteroids)
Immune suppression
Fig. 3. Summary of BHV-1 latency-reactivation cycle. For details, see the subsection 'Summary of the latency-reactivation
cycle in cattle'.
IE transcription unit 1 (IEtul) and IEtu2. IEtul encodes
functional homologues of two HSV-1 IE proteins, ICPO
and ICP4. IEtu2 encodes a protein that is similar to the
HSV IE protein, ICP22 (Wirth et al., 1991). In general, IE
proteins activate E gene expression, and then viral DNA
replication occurs. L gene expression is also activated
by bICPO, culminating in virion assembly and release.
As discussed above, bICPO is important for productive
infection because it transcriptionally activates all viral
promoters, .and is expressed at high levels throughout
infection (Wirth et al., 1991, 1992; Fraefel et al., 1994).
Acute infection leads to high levels of virus production
and secretion in ocular, oral or nasal cavities. If acute
infection is initiated in the genital tract, virus shedding can
be readily detected in genital'tissues. Regardless of the
site of infection, virus shedding can last for 7-10 days after
infection (Jones, 1998, 2003).
Summary of the latency-reactivation cycle in cattle
Viral particles, or perhaps subviral particles, enter the
peripheral nervous system via cell-cell spread. If infection
is initiated via the oral cavity, nasal cavity or ocular orifice,
the primary site for latency is sensory neurons within TG.
Relatively high levels of viral gene expression (Schang
and Jones, 1997) or infectious virus (Inrnan et al., 2002)
can be detected in TG from 1-6 days after infection (see
Fig. 3, for a summary of the latency-reactivation cycle of
BHV-1). Viral gene expression and detection of infectious
virus are subsequently extinguished, but viral genomes
can be detected in TG (establishment of latency). In
contrast to productive infection in cultured cells, a
significant number of infected neurons survive, and these
neurons harbor latent genomes. A hallmark of latency is
the abundant level of transcription that occurs from the
latency related (LR) gene (Jones, 1998, 2003; Jones et al.,
2006) and ORF-E (Inman et al., 2004). It appears that the
LR transcript is the first viral transcript expressed in
infected neurons because we have detected a spliced LR
transcript in TG at 24 h after calves were infected
(Devireddy and Jones, 1998). In contrast, we were not
able to detect IE or E gene expression at the same time
using sensitive RT-PCR assays, suggesting that LR gene
products play a pivotal role in programming the outcome
of virus infection in sensory neurons. Support for this
prediction comes from the finding that LR gene products
promote establishment of latency by inhibiting apoptosis
(Ciacci-Zanella et al., 1999; Henderson et al., 2004) and
viral gene expression (Bratanich et al., 1992; Geiser et al.,
2002). ORF-E may promote efficient establishment of
latency because it can induce neurite-like outgrowth in
mouse neuroblastoma cells (Perez et al., 2007). Consequently, ORF-E may enhance restoration of mature
neuronal functions following infection. During maintenance of latency, infectious virus is not detected using
standard virological methods. Since the LR gene and
ORF-E are abundantly expressed during the maintenance
of latency, they are predicted to play an active role in
maintaining latency.
Elevated corticosteroid levels (stress) and/or immune
suppression can initiate reactivation from latency. The
stress associated with moving cattle from one location to
another is one obvious stimulus that can trigger reactivation from latency and BRDC. During reactivation from
latency, three significant events occur: (i) productive viral
A review of the biology of bovine herpesvirus type 1 (BHV-1)
gene expression is readily detected in sensory neurons,
(ii) ORF-E and LR gene expression decrease dramatically
and (iii) infectious virus is secreted from nasal or ocular
swabs (Jones, 1998, 2003; Jones et al., 2006). Administration of dexamethasone to calves or rabbits latently
infected with BHV-1 reproducibly leads to activation of
viral gene expression and reactivation from latency (Rock
et al., 1992; Jones, 1998; 2003; Jones et al., 2000, 2006;
Inman et al., 2002). Although many latently infected
neurons do not apparently produce infectious virus, a
much higher number of neurons are detected in which
viral gene expression occurs (Rock et al., 19921, suggesting that virus-producing neurons are not common.
Non-neural sites of latency-persistence in cattle
Although establishment of latency in ganglionic neurons
is the main site of latency for BHV-1 and other
a-herpesvirinae subfamily members, latent or persistent
infections also occur in non-neural sites, tonsils and
lymph nodes for example. BHV-1 DNA is consistently
detected in tonsils (Winkler et al., 20001, peripheral blood
cells (Fuchs et al., 19991, lymph nodes and spleen of
latently infected calves, even when infectious virus is not
detected (Mweene et al., 1996). Pseudorabies virus (Sabo
and Rajanci, 1976; Cheung, 1995), equine herpesvirus
type 4 (Borchers et al., 1999) and canine herpesvirus type
1 (Miyoshi et al., 1999) DNA is also detected in lymphoid
tissue during latency. It remains to be seen what
non-neural cell types are latently infected with BHV-1,
and whether viral genes are expressed in these latently
infected cells. In contrast to latency in sensory neurons,
LR-RNA is not abundantly expressed in latently infected
lymphoid tissue (Winkler et al., 2000). Infectious virus can
be detected when germinal centers from tonsil of latently
infected calves are explanted (Perez et al., 2005) adding
support to the hypothesis that BHV-1 has established a
latent or persistent infection in cells of lymphoid origin.
The LR gene is abundantly expressed during latency
and is necessary for the latency-reactivation cycle
As discussed above, LR-RNA is abundantly transcribed in
latently infected neurons (Rock et al., 1987, 1992; Kutish
et al., 1990), and is antisense relative to the bICPO gene
(Fig. 1A). The lytic start site for LR-RNA is downstream of
the start site used in TG (Bratanich et al., 1992; Hossain
et al., 1995) (Fig. 1B). The LR gene has two ORFs (ORF-1
and ORF-2), and two reading frames that lack an initiating
ATG (RF-B and RF-C) (Fig. 1B). A peptide antibody
directed against ORF-2 recognizes a protein encoded by
the LR gene (Hossain et al., 1995;Jiang et al., 1998, 2004).
A fraction of LR-RNA is polyadenylated and alternatively
spliced in TG, suggesting that more than one LR protein is
expressed (Hossain et al., 1995; Devireddy and Jones,
1999). LR gene products ~nhibitcell proliferation, bICPO
RNA expression (Bratanich et al., 1992; Schang et al.,
1996; Geiser et al., 20021, and apoptosis (Ciacci-Zanella
et al., 1999). LR protein expression is necessary for
inhibiting apoptosis, but not cell growth (Geiser and
Jones, 2005) or bICPO expression (Bratanich et al., 1992;
Schang et al., 1996; Geiser et al., 2002).
A mutant BHV-1 strain with three stop codons at the
N-terminus of ORF-2 (Inman et al., 2001b) does not
express ORF-2 or RF-C following infection of bovine cells
(Jiang et dl., 2004). As expected, wt or the LR rescued
virus express ORF-2 and RF-C. Calves infected with the LR
mutant virus exhibit diminished clinical symptoms, and
reduced shedding of infectious virus from the eye, TG or
tonsil (Inman et al., 2001b, 2002; Perez et al., 2005). The
LR mutant virus does not reactivate from latency following treatment with dexamethasone, whereas all calves
latently infected with wt virus or the LR rescued virus
shed infectious virus following dexamethasone treatment
(Inman et al., 2002). Thus, the LR gene is necessary for the
latency-reactivation cycle in calves. It is not clear whether
LR proteins are necessary for stimulating reactivation from
latency or whether these products establish and maintain
latency in .a pool of neurons that are capable of
supporting reactivation from latency.
Previous studies determined that the LR transcript is
alternatively spliced in TG during acute versus latent
infections (Devireddy and Jones, 1998; Devireddy et al.,
2003). A novel alternatively spliced cDNA is expressed in
TG at 7 days after infection (7d cDNA), which is the
transition from acute infection to establishment from
latency. The 7d cDNA has the potential to encode the
N-terminal domain of ORF-2 fused to ORF-I, suggesting
that this novel fusion protein promotes establishment of
latency. The 7d cDNA was used in a two-hybrid screen to
identify cellular proteins that interact with the novel LR
fusion protein encoded by the 7d cDNA (Meyer et al.,
2007). The LR fusion protein interacts with two proteins
that can induce apoptosis (Bid and Cdc42), and with the
CCAAT enhancer-binding protein a (C/EBP-a). Bid links
the extrinsic pathway of apoptosis to the intrinsic
pathway because following cleavage by caspase 8, Bid
interacts with mitochondria (Li et al., 19981, which leads
to cytochrome c and Smac/Diablo release (Wang, 2001).
Bid is also specifically cleaved by granzyme B (Barry
et al., 2000; Alimonti et al., 2001; Pinkoski et al., 2001),
suggesting that the ability of LR proteins to interact with
Bid impairs cytotoxic T-lymphocyte (CTLI-induced death
of infected neurons. Neuronal stress, including removal of
nerve growth factor from neuronal cultures (Kanamoto
et al., 2000; Xu et al., 2001), induces Cdc42 activity, a Rho
GTPase family member (Harwood and Braga, 2003).
When PC12 cells (rat neuronal-like cell line) are treated
with nerve growth factor, they differentiate and behave
like mature sympathetic neurons (Greene and Tischler,
1976; Greene et al., 1987). If PC12 cells or primary
sympathetic neurons are deprived of nerve growth factor,
C. Jones and S . Chowdhury
Cdc42 is activated resulting in apoptosis (Kanamoto et al.,
2000; Xu et a/., 2001). Since dexamethasone is a potent
stressor and reproducibly induces BHV-I reactivation
from latency (Sheffy and Davies, 1972; Ackerrnann et al.,
1982; Homan and Easterday, 1983; Ackermann and Wyler,
1984; Brown and Field, 1990; Rock et al., 1992; Jones
et al., 2000; Winkler et al., 2002), Cdc42 may be activated
in TG.
The interaction between the LR fusion protein and
C/EBP-ol may also influence BHV-1 gene expression
because C/EBP-a stimulates lytic gene transcription of
other herpesviruses, EBV, HHV-8 and HVS for example
(Wang et al., 2003b; Wu et al., 2004; Wakenshaw et al.,
2005; Huang et al., 2006). Three lines of evidence support
the finding that C/EBP-a enhances BHV-I productive
infection: (i) C/EBP-a protein expression is stimulated
during productive infection, (ii) there is a positive
correlation between viral gene expression in TG and
C/EBP-a protein expression and (iii) wt C/EBI-'-a, but not
a DNA binding mutant, enhances BHV-1 plaque for~nation (Meyer et al., 2007). It will be of interest to determine
whether CIEBP-a directly stimulates viral promoters or if
it indirectly activates productive infection.
The BHV-I LR gene and HSV-1 LAT (latency-associated
transcript) share structural and functional properties. For
example, LR-RNA and LAT are transcribed in an antisense
direction of bICP0 and ICPO respectively, and both are
abundantly expressed during latency (Rock et al., 1987;
Kutish et al., 1990; Hossain et al., 1995; Schang and Jones,
1997; Devireddy and Jones, 1998; Winkler et al., 2000).
Furthermore, the LR gene (Ciacci-Zanella et al., 1999) and
LAT (Perng et al., 2000; Inman et al., 2001a; Ahmed et al.,
2002) inhibit apoptosis. To test whether the LR gene
restores spontaneous reactivation to a HSV-1 LAT deletion
mutant (dLAT2903), a 2 kb fragment containing the LR
promoter and LR coding sequences was inserted into
the LAT locus of dLAT2903, and the recombinant virus
designated CJLAT (Perng et al., 2002). Insertion of the LR
gene into the HSV-1 LAT locus restores high levels of
spontaneous reactivation in the rabbit eye model and in
explant-induced reactivation. Rabbits infected with CJLAT
have higher levels of recurrent eye disease (stromal
scarring and detached retinas). Further evidence for the
expanded pathogenic properties of CJLAT came from the
finding that CJLAT is more lethal in mice relative to LAT+
or LAT- strains of HSV-1. In contrast, insertion of the LR
gene with stop codons into dLAT2903 generated a virus
that behaves like the parental LAT-null mutant adding
further support that LR protein expression regulates the
latency-reactivation cycle (Mott et al., 2003).
ORF-E encodes a protein that is expressed in TG
of latently infected calves
A small ORF that is present within the LR promoter has
been designated OW-E (Fig. 1A). OW-E is antisense to
the LR transcript and downstream of the blCPO ORF. A
transcript that encompasses ORF-E is expressed in
productively infected bovine cells and TG of latently
infected calves (Inman et al., 2004). When ORF-E protein
coding sequences are fused in frame with green
fluorescent protein (GFIJ) sequences, GFP protein expression is detected in the nucleus of mouse or human
neuroblastoma cells. In contrast, the ORF-E-GFP fusion
protein is expressed throughout rabbit skin cells.
I'olyclonal antiserum directed against an ORF-E peptide
or the entire ORF-E protein specifically recognizes the
nucleus of sensory neurons in TG of latently infected
calves and mouse neuroblastoma cells transfected with an
OKF-E-expressing plasmid (Perez et ul., 2007). ORF-E also
induces neurite-like projections in these same mouse
neuroblastoma cells. In contrast, neurite-like projections
are not olxerved following transfection of rnouse
neuroblastoma cells with an empty vector, suggesting
that OIIF-E induces changes in the physiology of neuronal
cells. It mrill b e necessary to construct a BHV-1 mutant that
does not express the ORF-E protein to test whether ORF-E
plays a role in the latency-reactivation cycle.
Immune response to BHV-1 following acute infection
Although BHV-1 has the potential to immune-suppress
cattle, a potent immune response ultimately occurs,
which prevents systemic infection. With respect to BRDC,
this implies that immunosuppression initiated by BHV-1 is
short-lived.
The host immune response to BHV-1 jnfection includes
innate and adaptive immune responses (Rouse and
Babiuk, 1978). Innate immune responses include the
antiviral action of IFN, alternative complement pathway
and local infiltration of lymphoid cells, macrophages,
neutrophils or natural killer (NK) cells for example.
Following BHV-1 infection, IFN-a and IFN-P are
detectable in nasal secretions as early as 5 h postinfection, reach a maximum level at 72-96 h postinfection and can persist for u p to 8 days after infection
(Straub and Ahl, 1976). During early times after infection,
IFN-a and IFN-P promote leukocyte migration, activate
macrophages and increase NK cell activity (Babiuk et al.,
1985; Lawman et al., 1987; Jensen and Schultz, 1990).
Activation of macrophages and increasing NK cell activity
stimulate cytolytic activities against virus-infected cells
(Rouse and Babiuk, 1978). NK cells are a diverse
population of non-adherent effecter cells that lack T- and
B-cell markers (Cook and Splitter, 1989). These cells
require a long incubation period with the target cell for
optimum lysis (Campos and Rossi, 1986). In addition,
NK-like cytotoxicity is also associated with a population
of CD3' CD45', Fc receptor-positive lymphocytes, which
may represent a subset of y6 T-cells (Arnadori et al., 1992).
Adaptive or humoral immune responses lead to production of neutralizing antibodies that bind virus particles and
A review of the biology of bovine herpesvirus type 1 (BHV-1)
inhibit productive infection. Envelope glycoproteins gB,
gC, gD and gH are the most potent inducers of virus
neutralizing antibodies (Van Drunen Littel-van den Hurk,
1986; Marshall et al., 1988). In addition, non-neutralizing
antibody may mediate the destruction of enveloped virus
or cells expressing viral proteins o n the cell membranes,
and this process is referred to as antibody-mediated cell
cytotoxicity (Van Drunen Littel-van den Hurk et al., 1993).
Neutralizing and non-neutralizing antibodies produced
against envelope proteins can also inhibit virus infection by
several distinct mechanisms: (i) membrane attack complex
(MAC) lysis of virus envelope and virus-infected cells
mediated by antibody and complement and (ii) antibodymediated cell cytotoxicity in which either IgG interacts
with Fc receptor-positive cells (macrophages) or (iii)
binding of C3b to IgM mediates binding to C3b receptorpositive cells (lymphocytes, macrophages). In all cases,
virus-infected cells are lysed (Rouse et al., 1976, 1977a, b;
Rouse and Babiuk, 1977, 1978). Production of virus
neutralizing and non-neutralizing antibodies (IgG) can
be detected 8-12 days post-infection (Rouse and Babiuk,
1978). Local/mucosal immunity depends on secreted
neutralizing antibodies (IgA molecules) and systemic
humoral immunity depends on IgG.
Cell-mediated immune (CMI) responses play an
important role in killing virus-infected cells that express
viral antigens on the cell surface (Van Drunen Littel-van
den Hurk, 2007). For example, a C D ~ 'CTL response is an
important defense against BHV-I because cell-to-cell
spread in upper respiratory epithelium occurs before
hematogenous spread (Van Drunen Littel-van den Hurk,
2007). Cytotoxic and proliferatve T lymphocyte responses
occur in the blood approximately 8 days after infection.
CTL responses have been induced by gB and gD DNA
vaccines in mice (Deshpantle et al., 2002; Huang et al.,
2005). Further, gC and gD have been identified as targets
for CTL responses in cattle (Denis et al., 1993) and gB
DNA vaccines elicit a CTL response in cattle (Huang et al.,
2005). Other structural ancl non-str~ict~iral
vild proteins
may also play a role in CiVfI response because only a
limited number of BHV-1 proteins have been evaluated
for CTL activity (Van Drunen Littel-van den Hurk, 2007).
In addition to destruction of infected cells, T-lymphocytes
release a number of lymphokines that moclul;~tespecific
and non-specific immune response. For example, IFN-y
and other factors that further activate macrophages
(Campos et al., 1989) are produced. BIIV-I proteins
(gB-, gC-, gD- and VI'8) are recognizcd Ily CD-I' T helper
cells from immune cattle (Hutchings rt nl., 1990). Cells
expressing gB, gC or gD on their membranes have also
been identified as targets for cD4' T-cells (Leary and
Splitter, 1990; Tikoo et al., 1995a, b). Fhally, CDi' T-cells
are important for the developnlent of antibody response
and for developing effective CD8' T-cell memory
Uanssen et al., 2003; Shedlock and Shen, 2003). There'
C D ~ 'T cells as well as antibodies are
fore, both C D ~ and
required for long-term protection.
A prolonged CMI response occurs in the peripheral
nervous system during latency
Several independent studies have demonstrated that
T-cells, C D ~ 'T-lymphocytes in particular, control HSV-1
infection in sensory ganglia during latency (Nash et al.,
1987; Simmons and Tscharke, 1992; Simmons et al., 1992;
Cantin et al., 1995; Shimeld et al., 1995; Halford et al.,
1996; Liu et al., 1996; Shimeld et al., 1996, 1997). Viral
antigen-positive neurons surrounded by non-neural cells
expressing TNF-a, IL-2, IL-6, IL-10 or IFN-y can also be
detected in mice latently infected with HSV-1 (Halford
et al., 1996; Liu et al., 1996; Shimeld et al., 1997). No cells
with lymphoid cell morphology are detected in TG of
uninfected mice. A persistent infiltration of lymphoid cells
in sensory ganglia and spinal cord is also detected in mice
or guinea pigs latently infected with HSV-2 (Milligan et al.,
2005). Following infection of calves with BHV-1, foci of
infiltrating lymphocytes can be readily detected during
acute infection (Winkler et al., 2002). Finally, in human
TC latently infected with HSV-1, a chronic immune
response has also been observed (Theil et al., 2003;
Verjans et al., 2007). Collectively, these studies indicate
that long-term persistence of T-cells in sensory ganglia
during latency has the potential to regulate the latencyreactivation cycle.
Persistence of immune cells in TC may be due to
viral protein expression in a rare neuron or satellite cell.
Careful examination of TG neurons for viral gene
expression in HSV-1 latently infected mice (37-47 days
after infection) demonstrated that abundant viral transcripts, viral protein and viral DNA replication occur in
approxin~ately1 neuron per 10 TG (Feldman et al., 2002).
Infectious virus is not detected in these mice, confirming
that they are latently infected. Neurons expressing high
levels of HSV-1 transcripts are invariably surrounded by
foci of infiltrating white blood cells. The term 'spontaneous molecular reactivation' has been coined to describe
these rare neurons (Feldman et al., 2002). Rare cells in TG
of calves latently infected with BHV-I can be detected
that express viral transcripts and proteins (Winkler et al.,
20021, suggesting that mo~ecularspontaneous reactivation
occurs during BHV-1 latency.
CDH' T-cells that produce IFN-y are believed to play an
important role in preventing reactivation from latency in
sensory neurons in mice latently infected with HSV-1 (Liu
et al., 2000, 2001). Two independent studies have also
concluded that IFN-a and IFN-y control recurrent herpetic
lesions (Cunningham and Mikloska, 2001; Mikloska and
Cunningham, 2001). In addition to IFN, lymphocytemediated cytotoxicity could inhibit virus spread in TG.
Lymphocyte-mediated cytotoxicity induces two potent
apoptotic pathways: the granule exocytosis and the
Fas-Fas ligand pathway (Kagi and Hengartner, 1996;
Shresta et nl., 1998). The granule exocytosis pathway is
employed predominantly by CD8', NK and Iynlphokineactivated killer cells. It appears that the BHV-1 LR gene
C . Jones and S. Chowdhury
plays a role in regulating lymphocyte infiltration because
enhanced infiltration of lymphocytes occurs in TG of
calves acutely infected with the LR mutant virus (Perez
el al., 2006). The ability of dexamethasone to induce
apoptosis of inflammatory cells in TG of calves latently
infected with BHV-1 correlates with reactivation from
latency (Winkler et al., 2002).
BHV-1 vaccines
Many commercially available vaccines directed against
BHV-I can cause disease in sinall calves, in part because
these vaccines are immunosuppressive. Consequently,
certain vaccines have the potential to induce BRDC in
small calves. A discussion of the current status of BHV-1
vaccines and how they can be improved is included in the
following paragraphs.
Commercially available vaccines
I
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Commercially available vaccines directed against BHV-1
consist of modified live attenuated virus (MLV) or killed
whole virus (KV) (Van Drunen Littel-van den Hurk, 2005).
In many cases, MLVs are derived by serial passage
in tissue culture. KV vaccines are usually produced by
chemical treatments, such as formaldehyde, P-propiolactone or binary ethyleneimine MLVs generally induce both
humoral and cellular immune response because virus
replication in infected cells leads to presentation of viral
antlgen on MHC class I+ and 11' molecules. Safety is a
concern for MLVs because these strains can establish
latency and upon reactivation can be transmitted to
pregnant cows, which can lead to abortion. MLVs can also
be pathogenic in small calves because their immune
system is not fully developed, and most MLVs can be
immunosuppressive. KV vaccines are usually safe but
they are not as efficacious because they usually produce
only humoral immunity but no cellular immune
responses. Additionally, KV vaccines always require more
than one injection to achieve acceptable neutralizing
antibody levels. In the case of formaldehyde-inactivated
KV, antigens may also be denatured, which may affect the
immunogeniclty of vaccine preparations. KV also requires
suitable adjuvant formulations and some adjuvants may
induce injection s ~ t ereactions.
Commercially available BIN-I vaccines are primarily
evaluated on induction of neutralizing antibodies and the
duration as well as level of virus shedding following
challenge of vaccinated animals. As discussed earlier, the
CMI response against the virus is important to prevent
cell-to-cell spread of the virus. Therefore, a direct
measure of CMI directed against a vaccine virus is
important. Traditionally, IFN-y levels in vaccinated calves
have been an indicator of cellular immune responses.
However, a recent study demonstrated that there is an
increase in CD25 by C D ~ ' , C D ~ ' and y6T lymphocytes
from a BHV-1 MLV-vaccinated group (Endsley et al.,
2002). Therefore, increased expression of CD25, in
addition to IFN-y production by T-cells after vaccination,
appears to be a useful cellular immunity marker (Van
Drunen Littel-van den Hurk, 2007).
Recently, there has been an apparent increase in IBR
outbreaks in vaccinated feedlot cattle (commonly referred
to as vaccine outbreaks) (Van Drunen Littel-van den Hurk
et al., 2001; Ellis et al., 2005). Many of these vaccine
outbreaks occur in feedlots that have used several
different BHV-1 MLVs without serological markers,
suggesting that they are not vaccine-specific. Since the
vaccines used in the feedlots did not have any serological
marker, it is difficult to determine by serology whether an
animal is infected with an MLV or field strain. Thus,
determining the source of origin from a particular vaccine
break is not possible nor is it possible to test whether
these outbreaks were due to changes in the vaccine strain.
It is also possible that there is the emergence of a
new IBR strain that is not covered by existing MLVs. A
study investigating several isolates from such outbreaks
determined that at least one such isolate had mutations
within sequences comprising the gD-specific neutralizing
epitope (Van Drunen Littel-van den Hurk et al., 2001).
Development of genetically engineered
gene-deleted BHV- 1 vaccines
During the last 10-15 years, the usefulness of genetically
engineered gene-deleted vaccines has become increasingly apparent because they can be attenuated and
serologically distinguished from wt field strains (Van
Drunen Littel-van den Hurk, 2005). Numerous viral
mutants (gC-, gE-, gG-, Us9-deleted (Kaashoek et al.,
1998; Chowdhury et al., 1999; Butchi et al., 2007),
thymidine kinase (TIC)-deleted (Chowdhury, 19%;
Kaashoek et al., 1996a, b) and LR gene mutant virus
(Inman et al., 2002)) have been constructed and their
in uiuo pathogenic properties, reactivation properties and
immunogenicity analyzed. Based on recent studies, both
gE- and Us9-deleted viruses were safe in calves because
they do not reactivate from latency and they are highly
attenuated (Kaashoek et al., 1996a, b, 1998; Chowdhury
et al., 1999; Butchi et al., 2007; Liu et al., 2007). Studies
with gC-, gG- or TK-deleted viruses showed that they
either reactivate from latency and/or they retain some
degree of virulence (Kaashoek et al., 1996a, b, 1998).
Studies with a LR mutant virus showed that the virus does
not reactivate from latency and has reduced pathogenicity
in calves (Inman et al., 2002). Therefore, considering the
virulence and reactivation properties of gene-deleted
vaccine strains, gE-, Us9-deleted or the LR mutant
virus have the potential to be safer vaccine candidates.
Comparative vaccine efficacy studies showed that relative
to gC- and gG-deleted viruses, gE-deleted virus is less
A review of the biologv of bovine her~esvirustype 1 (BHV-1)
efficacious (Kaashoek et al., 1998). However, the
gE-deleted vaccine has been used successfully to eradicate IBR from a number of European countries.
Although the gE-deleted marker vaccine is not as
efficacious as others noted above, it will be used until a
better genetically engineered vaccine is developed.
Recent efforts to improve the IBR marker vaccine are
directed to delete viral gene sequences that are immunosuppressive. As noted above, gN inhibits TAP and
down-regulates MHC-I antigen presentation. Therefore,
a vaccine virus lacking the gN TAP binding domain may
stimulate better cellular immune responses. Our recent
studies show that a gE cytoplasmic tail truncated virus is
similarly attenuated in calves infected with the virus as the
entire gE ORF-deleted virus. Notably, like the gE-deleted
virus, the gE cytoplasmic tail truncated virus does
not reactivate from latency (Liu et al., 2007). Since the
cytoplasmic tail-specific amino acid sequences generate
antibodies that immunoprecipitate gE, antibodies specific
to the cytoplasmic tail sequence may serve as a serological marker t o distinguish vaccinated versus infected
calves (Whitbeck et al., 1996; Chowdhury et al., 2000).
Furthermore, the Us9 gene is located immediately downstream of the gE cytoplasmic tail gene; therefore, a
recombinant BHV-1 can be constructed in which the gE
cytoplasmic tail and the Us9 coding regions are deleted. A
vaccine virus that lacks US9, the cytoplasmic tail of gE, and
gN TAP binding domain may be a superior vaccine
candidate because it: (i) should stimulate better cellular
immune responses against BHV-1, (ii) will incorporate a
serological marker and (iii) should not be pathogenic.
Concerns have been raised about recombination occurring between two vaccine strains, which could lead to the
presence of virulent viral strains in vaccinated herds (Thriy
et al., 2005). Although it is clear that recombination can
occur, the process requires that both viruses must replicate
at the same time in the same cell of an infected calf.
Vectored vaccine strains
Intranasal vaccination of young calves with a replication
competent (E3-deleted) bovine adenovirus (BAV)-3
that expresses full-length BHV-1 gD inducecl protective
gD-specific neutralizing antibodies and cellular immune
responses (Zakhartchouk et al., 1999). Several studies also
concluded that gD-specific bacterial plasmid-based DNA
vaccines can serve as an effective subunit vaccine.
Specifically, an expression plasmid that encodes the
secreted form of gD (tgD) induces significant protection
against BHV-1 challenge following intraderrnal injection
(Van Drunen Littel-van den Hurk et al., 1998; Braun et nl.,
1999). Relative to killed BHV-I vaccine, the tgD DNA
vaccine induced significant IFN-y production In PBMCs.
Regardless of maternal antibody levels, the plasmid
encoding tgD also triggered neutralizing antibodies,
lymphoproliferative responses and IFN-y-secreting cells
in newborn lambs, suggesting that this approach may
be efficacious for neonate immunization (Van Drunen
Littel-van den Hurk et al., 1999).
Mucosal delivery of gB-based plasmid DNA vaccines
has also shown promising results. Delivery of plasmidbased BHV-1 gB DNA vaccine in the female vulvomucosal epithelium induced gB-specific antibodies and
cellular immune responses. Furthermore, vaccinated
animals have significantly reduced genital lesions upon
genital challenge (Huang et al., 2005). Recent studies
using a combined g R g D DNA vaccine in mice indicated
that mice immunized with the combined vaccine containing the secreted forms of the respective glycoproteins
developed higher titers of anti-BHV-1 neutralizing antibodies and increased cellular immune response compared to single plasmid injected groups (Caselli et al.,
2005).
Use of BHV-1 as a vaccine vector
BHV-1-based vectors have significant advantages relative
to other potential virus vectors for immunization of cattle
against economically important viral and bacterial
diseases, including those that initiate BRDC. Cattle are
routinely immunized against BHV-I and, therefore, the
use of BHV-1 as a vector would not pose a new risk to
cattle or humans. Gene-deleted BHV-1 strains could be
used to express other bacterial and viral gene coding
sequences. BHV-1 expressing the BVD (bovine diarrhea
<irus) gP53 (E2) protein has been constructed (Kweon
et al., 1999; Wang et al., 2003a). While the protective
efficacy of the BHV-1 vectored vaccine against BVD
challenge has not yet been reported, BHV-1 expressing
the E2 protein induced BVD gP53-specifc neutralizing
antibody in vaccinated calves (Kweon et al., 1999). BVD is
well known to be immunosuppressive and, like many
RNA viruses, can readily mutate (Peterhans et al., 2006).
Such complications from modified live BVD vaccines
could be avoided by using BHV-1 as live attenuated
vector to deliver BVD-specific protein(s). Similarly, BHV1-expressing bacterial proteins could be used to immunize against bacterial diseases that affect dairy and beef
cattle. These may include Mannheimia hemolytica protective antigens, which are a significant cause of pneumonia
that occurs as a result of shipping fever. Similarly,
Mycobacteriz~m avit~m subspecies paratuberctllosis
(MAP) is a slow growing bacterium with zoonotic
potential (Grant, 2005). Development of an effective
vaccine is hindered due to its extremely slow growth and
difficulties in protective bacterial antigen purification.
Several mycobacterial proteins trigger cellular immune
responses (Rossels et al., 2006), which are important for
protective immunity against MAP. BHV-1-expressing MAP
proteins would certainly have a potential as a vaccine
against MAP and BHV-1. Although BHV-1 can be used as
a potential vector for delivering foreign antigens to calves,
.
C. Jones and S. Chowdhury
a thorough understanding of t h e immune-suppressive
nature of BHV-1 a n d t h e latency-reactivation cycle is
essential.
Acknowledgments
The laboratory of CJ is s u p p o r t e d by t w o USDA grants
(2005-01554 a n d 2006-01627), a grant from NIAID
(~21AI069176)a n d , i n part, a Public Health Service grant
1 ~ 2 0 ~ ~ 1 5 6t o3 5 t h e Nebraska Center for Virology.
The laboratory o f SC is s u p p o r t e d by t w o USDA grants
(00-02103 a n d 2004-35204-14657).
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