D8538.PDF

Rev. sec. tech. Off. int. Epiz., 1986, 5 (4), 869-878.
Infectious bovine rhinotracheitis/infectious
pustular vulvovaginitis: BHV-1 infections
H. LUDWIG* and J.-P. GREGERSEN**
Summary:
This short review article summarizes
recent information
on the
molecular biology of bovine herpesvirus 1 (BHV-1) and the IBR-like as well as
IPV-like
genomes.
This may provide
a better understanding
of
BHV-1
latency.
DNA fingerprinting
of isolates allows us to trace diseases and gain a pic­
ture of the molecular epizootiology.
The major immunogenic proteins,
espe­
cially a 74 Kd glycoprotein
which gives rise to neutralizing antibodies,
have
been defined as those structural components
being involved in
cross-reactions
with the goat herpesvirus (BHV-6) and being of importance for
diagnostic
assays.
Besides the known clinical appearance of BHV-1 infections,
expressing
themselves mainly as respiratory or genital infections, the immune response is
discussed and its value outlined for diagnostics and
epizootiology.
In conclusion,
infections.
recommendations
are given to control
or eradicate
BHV-1
KEYWORDS: Bovine herpesvirus - Cattle diseases - Immunity - Latent infection Viral diseases.
INTRODUCTION
This review gives a synthesis of clinically orientated data with recent informa­
tion on molecular biological and immunological research in this field. A more pre­
cise understanding of the genetics and immunological function of bovine herpes­
virus 1 (BHV-1) may have consequences for prophylactic and control measures con­
cerning the corresponding diseases.
Previous reviews on these cattle diseases and the infectious agent, bovine her­
pesvirus 1, deal in more detail with clinical aspects (24, 13, 21, 43, 29) or the latest
biological aspects of the virus (26).
HISTORY
In continental Europe the genital form of BHV-1 infection has been known for
more than 100 years. The first reliable report stems from Rychner (39) in Switzerland
who mentioned, in 1841, a venereal disease (in a bull and several contact cows) which
was subsequently referred to as "Bläschenausschlag" (45) or "Exanthema
* Institute of Virology, Free University Berlin, Nordufer 20, 1000 Berlin 65, FRG.
** Virologische Forschung Behringwerke AG, 3550 Marburg 1, FRG.
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vesiculosum/pustulosum coitale" (51, 49). Reisinger and Reimann (37) were the
first to show the filterability and transmission of the infectious agent, demonstrat­
ing that this disease was not of bacterial origin. It took thirty years for the virus to
be isolated and it was then named "infectious pustular vulvovaginitis (IPV)" virus
(23, 18).
In contrast to this clinical picture, infectious bovine rhinotracheitis (IBR) was
first described in the 1950's in Colorado and California (40) from whence it spread
rapidly. The close antigenic relationship between IBR and IPV viruses and the
induced clinical pictures were recognized by Gillespie et al. (14). In 1960 the first
case of an IBR virus infection was reported on the European continent (19), fol­
lowed by descriptions of this respiratory tract infection in the United Kingdom and
in other countries. Further tracing of these infections throughout the world was
(and still is) hampered by the fact that serological surveys performed subsequently
in different countries could not distinguish between IBR- and IPV-virus infections
because of the antigenic cross-reactivity. No fundamental distinction was made bet­
ween the genital and respiratory manifestations of the virus, and they have been
indiscriminately called IBR-IPV virus infections since that time.
CLASSIFICATION A N D BIOLOGY OF T H E VIRUSES
Genetic material
The IBR/IPV viruses have been classified as BHV-1. This is based on serology.
Their identity was later proved by DNA studies. With certain restriction enzymes
such as 'HpaP, however, a clear separation into IBR-like and IPV-like strains is
possible, grouping all the foetal isolates, some of the brain isolates, and abortigenic
viruses with the IBR-like viruses (26). Different findings with viruses from other
countries (34, 7, 32), where the classical picture of European IPV is not known or
has become modified, most probably reflect rapid changes of the viruses in cattle
populations.
BHV-1 does not cross-react with BHV-2 (bovine herpes mammillitis virus), with
the African malignant catarrhal fever virus (tentatively grouped as BHV-3) or with
BHV-4 (the Movar-type virus) (26, 46). Caprine herpesvirus (tentatively grouped as
BHV-6; 10) is antigenically and serologically closely related to BHV-1, but clearly
differs in DNA fingerprinting.
The BHV-1 genome is similar to that of Pseudorabies virus, equine herpesvirus
types 1 and 3, and varicella-zoster virus, belonging to the class D herpesviruses. The
BHV-1 genome has a molecular weight of 135 Kd and is known to be composed of
a unique short (Us; 13 Kd) sequence which inverts relatively to the unique long (UL;
100 Kd) sequence, leading to two isomeric forms of DNA which are flanked by
internal (11 Kb) and terminal repeats (11 Kb). Recent findings show that the BHV-1
genome has a small unique DNA "tail" on the terminal repeat sequence
(Hammerschmidt, personal communication) which might be involved in replication
and could turn out to be important for the latency of the virus. Short repeats in
BHV-1 DNA terminal fragments which are responsible for the heterogeneity of the
genomes appear to play a role in the circularization or concatamerization of the
viral genome during DNA replication and subsequent cutting. Although BHV-1
replication is far from being understood, genome structures of this virus have
proved to be a good model of the general properties of herpesviruses, e.g. the ter­
minase cleaving the DNA into the right genome length size (20).
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Proteins and antigens
BHV-1 induces approximately fifty infected cell proteins, about thirty of which
are structural proteins of the virus, and approximately fifteen are non-structural
polypeptides. Eight to eleven are glycosylated (33). The glycoproteins appear on the
outer envelope of viral particles as well as on the surface of infected cells and repre­
sent the main target for the immune system, inducing a response which may neutra­
lize free virus and destroy infected cells.
BHV-1 glycoproteins are divided into three groups, each consisting of two or
three polypeptides which appear to be different forms of the same basic molecule,
i.e. as a monomer or dirner or as a precursor and its final products (47, 28). It
emerged from different studies — and was essentially pointed out for the first time
by Gregersen (15) — that a glycoprotein with a molecular weight between 74,000
and 82,000 represents the main immunogenic component, which induces the strong­
est neutralizing immune response (8, 16, 28). Therefore, we believe that the 74 Kd
glycoprotein is the most suitable candidate for a possible future subunit or recombi­
nant vaccine. Antibodies against other glycoproteins seem to neutralize BHV-1
weakly or only in the presence of complement (16, 28).
BHV-1 strains of different origin and pathogenicity exhibit a high degree of uni­
formity in their protein composition, although strain-specific differences were
observed with some minor polypeptides (16, 31). It is of special interest that the
goat herpesvirus (BHV-6) shares the major immunogenic glycoproteins with BHV-1,
which is the reason for strong immunological cross-reactivity and a marked one-way
cross-neutralization of BHV-6 by antibodies directed against BHV-1 (10, 15, 22, 25).
CLINICAL MANIFESTATIONS
BHV-1 infections are known as the classical picture of infectious pustular vulvo­
vaginitis (or infectious balanoposthitis in bulls) and typical infectious rhinotracheitis.
IBR is associated with more or less severe affliction of the respiratory tract. The
pathological pictures vary from slight inflammation of the mucous membranes to
severe alterations in the tissue of the respiratory tract. Simultaneous infection with
other viruses (paramyxo-, rhinovirus) or bacteria may result in bronchopneumonia.
In conjunction with respiratory illness, conjunctivitis is a frequent event which can
lead to keratoconjunctivitis ('pink eye'). Another rare form of BHV-1 infection is
encephalitis in the calf, seldom seen in adult bovines (12). Recently, variant viruses of
BHV-1 have also been isolated from a neurological disease of calves in Argentina
(32). BHV-1 has also been reported to cause abortions (30). In this context, it should
be mentioned that live attenuated virus vaccines led to abortions, especially in the
USA. We identified abortigenic viruses to be of the IBR type (16). In contrast, live
virus vaccines based on IPV-like viruses were non-abortigenic (26).
The typical clinical entity defined as IPV (or as "Bläschenausschlag" in Germanspeaking countries) was widespread in small farms in Europe where the bull transmit­
ted the disease. A circumscribed exanthema on the vulva and in the vagina, or bala­
noposthitis in male bovines, is associated with pustules followed by necrotic erosions
of the genital mucosa. Good healing tendency appears to be typical.
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The clinical appearance of BHV-1 infections has changed in the past decade.
With the introduction of artificial insemination, IPV has become rare whereas IBR
is now the prominent clinical entity, distributed world-wide in cattle. Rapid trans­
mission of IBR-like viruses in large herds under crowded conditions may have led
to variations in IBR virus isolates, identified by DNA fingerprinting. It is conceiv­
able that viruses able to spread easily, and having a high replication rate, extensi­
vely use their genomic ability of variability (20).
IMMUNE RESPONSE
Humoral immunity
This is the most prominent immune response, and measurement of neutralizing
antibodies is usually taken as the sole parameter for the immune status. Although
neutralizing antibodies against the 74 Kd and a 90 Kd glycoprotein clearly reflect
that an infection has taken place in the herd (16, 28), it is conceivable that BHV-1
infections without neutralizing antibodies can be traced by using sensitive ELISA
tests. In all assay systems except for the neutralization test, cross-reactions with
other bovine herpesviruses have always raised doubts concerning the specificity of
the reactions.
More refined methods and further investigations are necessary to definitely cla­
rify this point. In the meantime, the neutralization test positive with 1:2 diluted
serum can be regarded as proof of infection in a herd. A cross-reactivity of BHV-1
with BHV-6 might cause diagnostic problems in countries where goats and cattle
are tested. Both viruses induce a strong cross-neutralization response, although the
response is always stronger in the homologous system (22).
As in other herpesvirus systems, even a strong humoral immune response does
not prevent BHV-1 latency. The status of the immune response, however, is be­
lieved to control the amount of activated virus. In any case, each recurrence boosts
the existing antibodies. In general, one should consider that the humoral immune
response only partly reflects the immune status, and that the cellular immune res­
ponse, which has been less investigated, might play a more important role in
defence against the disease.
Cell-mediated immunity
A strong humoral immune response may neutralize free virus, but BHV-1 can­
not be eliminated from the body. In vitro models where infectious virus spreads
from cell to cell in the presence of neutralizing antibodies exemplify the situation in
the animal. Although little is known about the cellular immune response against
BHV-1, several mechanisms attack infected cells, such as a specific cell-mediated
immunity by helper and suppressor T-lymphocytes and cytotoxic T-cells as well as
their precursors, and a non-specific response by natural killer cells and antibodydependent cellular cytotoxicity (ADCC). A balanced activation of such lymphocytic
sub-sets — as achieved by replicating virus — is essential for an effective T-cell res­
ponse. Non-replicating herpesviruses and their glycoproteins are weak antigens for
the stimulation of a cellular immune response (38). This may explain why inactiv­
ated BHV-1 vaccines were considered to be less effective than live virus vaccines.
However, an increased amount of antigen, a better presentation of inactivated anti­
gens, and appropriate adjuvants may lead to sufficiently effective inactivated vaccines.
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The fact that newborn calves are more susceptible to BHV-1 infections, and more
often show severe clinical signs including encephalitis, may be due to immature cel­
lular immune functions.
Testing for the delayed type of hypersensitivity enables us to detect a T-cell
immune response in vivo (9) even if neutralizing antibodies are not traceable (3).
Because the required simple and sensitive routine methods for testing cell-mediated
immunity are not commercially available, we are still unable to define the real
immune status of BHV-1 infected animals.
Local immunity
Humoral and cellular immune mechanisms cooperate in eliminating infectious
virus, and are thus of major importance for the epizootiology of BHV-1 infections,
whereas local immunity strongly influences the severity of the disease in the infec­
ted individual.
Non-specific defence mechanisms (i.e. anatomical structures, mucus, cilia,
interferon, macrophages), locally produced antibodies and a local cell-mediated
immune response all cooperate at mucous membranes and comprise the local
immunity. Among different secretory immunoglobulins IgA predominates (5). It is
mainly effective in the upper respiratory tract, whereas cellular mechanisms could
play a major role in recovery from severe lung infections. Natural and artificial
BHV-1 infections induce the production of interferon on respiratory and genital
mucous membranes (4) where it contributes directly, or by the stimulation of other
immune mechanisms, to an early immunity (44, 48).
Immunosuppression
Recent immunological studies indicate that the immune response against a
BHV-1 infection not only stimulates, but also partly inhibits immunological func­
tions, leading to an increased susceptibility for secondary bacterial infections (50).
BHV-1 infections have been reported to suppress the chemotactic response of neu­
trophils, natural cell-mediated cytotoxicity, and the responses of peripheral blood
lymphocytes to mitogens. Decreased immunological functions against secondary
respiratory bacterial infections were also observed when no cell damage on respira­
tory mucous membranes could be noted after intramuscular application of virus
(11). Live virus vaccines may have a similar suppressive effect on the immune res­
ponse in cattle.
EPIZOOTIOLOGY
Infectious pustular vulvovaginitis or balanoposthitis was the only clinical form
of BHV-1 infection seen during the century which followed its first description.
Transmission of virus occurs from individual to individual by direct genital contact.
Therefore this disease spreads relatively slowly. In regions where only small cattle
herds are kept and artificial insemination is not exclusively performed, the situation
has not changed much. Artificial insemination has drastically reduced the IPV
cases.
BHV-1 gained major economic importance when a virus variant, which caused
severe respiratory infections, appeared in the late 50's. This virus spread rapidly in
feedlots and in cattle populations with high fluctuation. Exports of cattle and
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semen from the United States to almost every continent subsequently spread the
new respiratory disease all over the world. Virus latency has certainly contributed
as a co-factor to its efficient distribution. This reconstruction of events can be
deduced from recent molecular epizootiology based on restriction enzyme analysis
of BHV-1 DNA's in selected isolates with known disease history. The results
demonstrate differences between IBR and IPV isolates. With a suitable restriction
enzyme (e.g. Hpal), discrimination between the classical IPV-like and IBR-like
virus strains is possible. IBR-like viruses seem to be more pathogenic since isolates
from abortions and encephalitis are associated with the IBR-like Hpal restriction
pattern (16). It should be noted that IPV viruses can cause mild respiratory diseases
and vice versa, IBR strains have been isolated from the genital tract (14), which fur­
ther complicates the situation. IBR viruses among themselves exhibit a striking
homology, confirming the theory that a single variant was originally responsible for
the sudden appearance of respiratory infections. On the other hand, IPV isolates
show a divergence within their DNA-fingerprints, which indicates that different
virus types may have developed within decades. Although the appearance of new
strains with altered pathogenicity seems to be rather a rare event, BHV-1 is not
totally stable. The recent findings that a specific neuropathogenic strain from calves
has a different genome pattern (7, 32) indicate that another highly pathogenic IBR
virus variant has developed.
Distribution
BHV-1 occurs throughout the world. Infections occur regularly in European,
Northern American and some African countries, as well as in Australia. Although
reports from certain Asian, African and South American countries are not avail­
able, it can be assumed that BHV-1 infections are also present in those regions, but
are simply not diagnosed or not reported because other diseases are more impor­
tant. Apart from cattle, neutralizing antibodies against BHV-1 have also been
found in other animals, partly phylogenetically related, like goats, buffaloes, wilde­
beest, red deer and other free-living wild ungulates. We cannot prove that these
antibodies are induced by BHV-1 infections because they might have been origin­
ated by other cross-reacting herpesviruses.
Latency and reactivation
A general feature of all herpesviruses is their ability to remain latent. This topic
is discussed in detail by Thiry et al. in this issue. Here, the major characteristics of
latent BHV-1 infections and their consequences for efficient disease control are
summarized. Viral latency must be considered as a regular event, and is certainly
not exceptional. It is accepted that the regional ganglia are a major site for latency.
The virus persists there as a DNA copy (1, 2). Other sites for latent virus may exist,
because BHV-1 has been isolated from normal calf foetuses (27).
Reactivation of latent BHV-1 occurs spontaneously under the influence of natu­
ral stress factors (diseases, transportation, parturition), or may be induced artifi­
cially by corticosteroid treatment (41, 36). Reactivated virus may cause recrudes­
cence of the disease and virus is shed from the local mucous membranes as well as
in semen from bulls (17). Problems and principles concerning latency and reactiva­
tion are also valid in cases where live virus vaccines are used. It is well accepted that
antiviral antibodies have no effect on latency and recrudescence. Humoral anti­
bodies do not prevent the establishment of latent infections (35, 42), but may
reduce the amount of excreted virus, and may influence the course of recrudescent disease.
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Latency after BHV-1 infections or live virus vaccination is an obstacle for the
control of this disease. It reduces the value of diagnostic efforts since successful
virus isolation or the presence of antibodies (or a fourfold increase of antibody
levels) do not always indicate an external infection. It may also indicate reactivation
of a latent infection. Furthermore, an animal once infected must be considered as a
virus carrier for years, and thus a potential source of infection for other indivi­
duals.
PROPHYLAXIS A N D DISEASE CONTROL
Sensitive and simple diagnostic methods are a basic requirement for the success­
ful control of IBR/IPV infections. Neutralization tests and virus isolation are used
mainly to detect infected animals or virus carriers. Both methods are rather tedious,
require the use of cell cultures and thus can only be performed in laboratories with
appropriate experimental equipment and highly-trained personnel. Neutralization
assays should be done as a plaque reduction assay using not more than 100 plaqueforming units per assay, and should start with at least a 1:2 dilution of inactivated
serum to guarantee maximum sensitivity. The detection of chronic virus carriers by
virus isolation should be conducted after prior activation of a latent infection by
corticosteroid treatment of animals. Virus neutralization tests and virus isolation
followed by virus neutralization with a specific antiserum give the highest specifi­
city. However, ELISA or RIA tests are more practical and are used for testing large
numbers of blood or milk samples, although their specificity may be some­
what lower. Their advantage is higher sensitivity, which may be useful for detecting
low antibody titres in latently infected animals.
The delayed hypersensitivity test may be very useful, too, for detecting latent
infections, but this test is still at the experimental stage. It is important for the test
not to evoke humoral antibodies which could interfere with serological antibody
tests. None of these test procedures differentiates between IBR and IPV virus infec­
tions, although, in several countries, the governmental regulations treat venereal
(IPV) and respiratory (IBR) diseases differently. Normally, only genitally transmit­
ted BHV-1 infections are subject to regulations. It should be recommended that
both diseases be controlled without distinction.
Successful disease control may be achieved by the following
measures:
1. Elimination of risk factors by artificial insemination, separation of positive
from pre-tested negative animals, export restrictions for BHV-1 positive animals,
and embryos or semen from positive animals.
2. Establishment of BHV-1 free herds. This includes serological testing twice a
year, removal of positive reactors and strictly separate handling of animals from
positive and negative herds. Breeding cattle and bulls in artificial insemination cen­
tres should be kept apart in units composed of animals free from virus and anti­
body.
3. Animals in BHV-1 positive herds may be vaccinated, if at all, preferably with
inactivated vaccines to avoid the risk of latent infections. Live virus vaccination
should be avoided. The only indication for application of live attenuated vaccines is
a direct danger of infection in a certain herd.
The aim of successful disease control should be the absence of virus, and not
just of disease. Thus, an early decision as to whether to combat disease or to elimi-
—
876 —
nate the infectious agent is required, because the control of overt disease by vacci­
nation interferes with the total elimination of the infectious agent. A complete,
organized strategy is a fundamental condition to achieve control of BHV-1 infec­
tions.
*
* *
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