D8240.PDF

Rev. sci. tech. Off. int. Epiz., 1990, 9 (1), 13-23.
Bovine virus diarrhoea virus:
an introduction
M.C. HORZINEK *
Summary: In view of the recently established genome organisation of
pestiviruses, their classification as members of the togavirus family is no longer
tenable. They should rather be provisionally considered as a new genus of the
Flaviviridae, irrespective of differences in the nonstructural genes. Like other
positive-stranded RNA viruses, pestiviruses are highly variable; apart from point
mutations, recombinations are expected to contribute to their capricious
behaviour. One trait of expected pathogenetic significance in infections with
bovine virus diarrhoea virus is a change from the non-cytopathogenic to a
cytopathogenic biotype. Cooperation of both variants in an animal to produce
the severe disease picture known as mucosal disease is unique in virology;
elucidation of this mechanism may shed light on the pathogenesis of other
sporadic diseases with suspected viral origin.
KEYWORDS: Antigenic variation - Biotypes - Bovine virus diarrhoea virus Flaviviridae - Monoclonal antibodies - Mucosal disease - Pestivirus Polypeptides - Taxonomy.
M o r e t h a n forty years have passed since Olafson et al. (42) and Childs (9)
simultaneously published descriptions of an acute enteric disease in cattle which was
later found to be caused by a virus (46, 52). T h e disease was designated bovine viral
diarrhoea (BVD), and the causative agent was given the graceless and redundant name
bovine viral diarrhoea virus (BVDV). Some years later, the same virus was also
implicated in causing " m u c o s a l disease" (MD), a fatal condition first described by
Ramsey and Chivers (49). Again a n ominous and confusing terminology emerged,
when aetiologically diverse but clinically similar syndromes were a c c o m m o d a t e d in
the " m u c o s a l disease c o m p l e x " : foot and m o u t h disease, rinderpest, malignant
catarrhal fever and others. Fortunately, this designation is now obsolete. The M D
which follows BVDV infection occurs in cattle that are persistently infected and
immunotolerant to the virus; tolerance is established in the fetus during early
pregnancy following transplacental infection. This hypothesis (34) has subsequently
been supported by both experimental and epidemiological findings, and its molecular
basis is about to be unraveled. A review on BVD has recently been published by Liess
(32).
* Department of Virology, Institute of Infectious Diseases and Immunology, Veterinary Faculty,
Yalelaan 1 (de Uithof), 3508 TD Utrecht, The Netherlands.
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T H E N E W T A X O N O M I C POSITION OF B V D V
For a long time, viral t a x o n o m y was based exclusively o n structural features of
the infectious particle. Three alternative criteria were used: the type of nucleic acid
( D N A or R N A ) , the lipoprotein envelope (present or absent) and the nucleocapsid
symmetry type (icosahedral or helical). While the first two features of a virus are
easily established — using nucleic acid inhibitors and organic solvents or detergents,
respectively - identification of the symmetry type in enveloped virions is less
straightforward. This requires electron microscopic analysis after selective removal
of the virion m e m b r a n e , an a p p r o a c h that led to the identification of icosahedral
capsids in the arthropod-borne alphaviruses (25) and in other, then unclassified, small
enveloped viruses without conspicuous a r t h r o p o d transmission (26).
In recent years, there has been a tendency to a b a n d o n strictly structural criteria
of classification and to m a k e use of other properties, e.g. the replication strategy
of viruses. This is a rational approach if t a x o n o m y is to reflect evolutionary
relationships. After all, more constraints and more selective pressure may be expected
to operate at the level of the extracellular virus particle, its proteins and antigenic
determinants t h a n , e.g., at the level of m R N A transcription; the m o d e of replication
is probably better conserved during evolution.
In 1973, the present author coined the term "pestiviruses" to group two
antigenically related enveloped R N A viruses: hog cholera virus (HCV) and BVDV
(22). A third animal pathogen, the Border disease virus of sheep, was later found
to be a close relative of BVDV. In its fourth report published in 1982 for the Virology
Division of the International U n i o n of Microbiological Societies (IUMS), the
International Committee on Taxonomy of Viruses (ICTV) adopted this nomenclature
and assigned generic status to the pestiviruses, with BVDV as the prototype (36).
Pestiviruses are amongst the smallest enveloped animal R N A viruses (measuring about
40 n m in diameter) and possess a nucleocapsid of non-helical, probably icosahedral
symmetry (26). They share these traits with numerous flaviviruses, of which the
mosquito-transmitted yellow fever virus is the prototype (the pestiviruses are nonarthropod-borne). Previously, the flaviviruses also held generic status in this family,
b u t when details of their molecular structure, replication strategy and gene sequence
became known in the early 1980's, the Togavirus Study G r o u p acknowledged the
differences as fundamental and established the new family Flaviviridae - with
flavivirus as its only genus (56).
In view of recent progress in the description of the molecular features of
pestiviruses, the discussion of virus classification must now be re-opened. The first
molecular data which suggested that pestiviruses are distinct from members of the
Togaviridae family relate to characteristics of the virus-specific R N A . In infected cells,
only a single high molecular weight species was found which lacked a 3' poly(A) tract
(47, 5 1 ; M o o r m a n n , personal communication). N o subgenomic R N A was detected
at any time after infection. These properties distinguish pestiviruses from togaviruses
- of which b o t h the alpha- and rubiviruses possess one subgenomic R N A - a n d
suggest a similarity to flaviviruses. Much of the nucleotide sequence and genetic
organisation of BVDV is known, and further comparisons with flaviviruses have been
m a d e (10). With the exception of several short but significant stretches of identical
amino acids within two of the putative nonstructural proteins, n o extended regions
of homology exist between BVDV and representatives of the three antigenic subgroups
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of mosquito-borne flaviviruses. Nevertheless, the molecular layout of the BVDV a n d
flavivirus genomes is strikingly similar. Comparison of the arrangement of the proteincoding domains along b o t h genomes and the hydropathic features of their amino
acid sequences revealed pronounced similarities. Based o n these comparisons, it was
proposed that the Pestiviruses n o longer be grouped in the Togaviridae family, b u t
rather be considered a genus within the Flaviviridae (10).
F o r such a proposal t o be accepted, additional molecular d a t a for other BVDV
isolates (and other pestiviruses) will be required. However, the implications of this
proposition are immediately provocative. Considering the parallel organisation of
their genomes, analogous polypeptides m a y be predicted to possess similar biologic
functions. Examples corroborating this hypothesis have been given in our recent review
on molecular advances in pestivirus research (12). Drawing analogies to the flaviviruses
m a y help in experimental designs to resolve the issue of structural vs. nonstructural
proteins for pestiviruses. Certainly insights beyond those in molecular biology m a y
be gained from further comparisons between these two groups of viruses.
N o n - a r t h r o p o d - b o r n e togaviruses were last reviewed in 1981, when only limited
molecular d a t a were available (23). Meanwhile, expanding knowledge has m a d e
another earlier classification untenable: equine arteritis virus (EAV) which has been
listed as a possible member of the Togaviridae family (36) replicates via multiple
subgenomic m R N A ' s (54); they form a 3'-coterminal nested set, not unlike t h a t in
coronaviruses (Spaan and Horzinek, unpublished observations) and toroviruses (53).
However, by possessing an enveloped icosahedral nucleocapsid, E A V meets the
structural criteria of a togavirus. The presence of two " i n c o m p a t i b l e " taxonomic
elements in one virus indicates that our concept of classification is certainly too narrow;
however, it m a y also indicate convergent evolution (24).
T H E RECENT HISTORY OF RESEARCH ON B V D V
It was an old and enigmatic finding that fatal M D , one of the consequences of
BVDV infection of cattle, could not be reproduced experimentally, thereby defying
Koch's postulates. The conditions which must be met for M D t o develop have now
been defined. Cows infected during the first four m o n t h s of gestation with BVDV
can give birth to healthy, persistently viraemic calves (7, 33). W h e n this virus is of
a non-cytopathogenic (ncp) biotype, superinfection with a " m a t c h i n g " cytopathogenic
(cp) strain of BVDV will result in the severe M D condition (3, 4, 6). It has been
suggested that M D m a y be a consequence of the in vivo conversion of the ncp strain
(the one that causes persistent infection) to cytopathogenicity (7, 27), which would
explain the erratic and sporadic occurrence of M D in a cattle population. As will
be discussed below, the cp and ncp strains differ in the expression of at least one
polypeptide.
Antigenic variation and epitope mapping
Since the historic observation by Darbyshire (15) that H C V and BVDV are
antigenically related, n u m e r o u s attempts have been m a d e to elucidate the degree and
the basis of serological cross-reactions. A l t h o u g h most workers agree t h a t each
pestivirus is antigenically homogeneous, i.e. that serotypes of H C V , BVDV or Border
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disease virus do not exist (8), analyses using conventional antisera have shown strain
variations within each pestivirus detectable by cross-neutralisation tests (2, 41).
Neutralisation assays are also able to distinguish between H C V and BVDV, but not
between BVDV and Border disease virus. This latter distinction must be based o n
biological and epidemiological data (30).
Monoclonal antibodies (MAB's) now provide the tools for a more detailed analysis;
they have been characterised as to their spectrum of reactivity with different pestivirus
strains and isolates, their virus neutralising capacity and their protein specificity.
Preparation of the first M A B ' s to BVDV was reported by Peters et al. (44) and
to H C V by Wensvoort et al. (55). The former antibodies were found to be specific
for p l 2 5 of ncpBVDV. W h e n analysed with cpBVDV, they reacted with b o t h the
p125 and p80 found in cells infected with this biotype (Bolin and Moennig, unpublished
observations). When tested against other pestiviruses using indirect
immunofluorescence and peroxidase-linked antibody tests, some of these M A B ' s
recognised only cpBVDV, while others reacted broadly with all BVDV isolates a n d / o r
with b o t h Border disease virus and H C V (20). One antibody (BVD/C16) was
pestivirus-specific, reacting with all fifty pestivirus isolates tested at this point. These
results suggest that sequences within the p125 are well conserved among pestiviruses.
The limited genomic sequence d a t a available indicate that the conserved component
is p80 (see below). This protein probably represents the soluble ( " S " ) antigen forming
the "single line of identity" observed by Darbyshire (15) in agar gel immunodiffusion
tests with H C V and BVDV specific antisera. Dubovi (personal communication) has
characterised a M A B specific for a minor glycoprotein (gp48) of BVDV which reacted
with all pestiviruses tested, including one strain of H C V . Additional M A B ' s with
b r o a d anti-pestiviral activity have been generated (Chappuis, Edwards, Nettleton,
unpublished results); their protein specificity is not yet k n o w n .
A number of M A B ' s directed against the major glycoprotein of BVDV and H C V
(gp50-59, referred to hereafter as gp53; see Table I in ref. 12) were shown to possess
virus neutralising activity. M A B ' s specific to gp53 of BVDV lacking neutralising
activity have also been described (17; Moennig and Bolin, unpublished observations).
Of the former M A B ' s , most neutralised several isolates of the homologous virus,
but not of other pestiviruses (5, 17; Coulibaly, unpublished observations; Wensvoort,
unpublished observations). Interestingly, however, some M A B ' s which neutralised
one isolate did bind to another virus without neutralising its infectivity (Mateo and
Moennig, unpublished observations). A similar p h e n o m e n o n was recently described
for Sindbis virus and some of its variants (43). T h u s , the significance of conserved
epitopes for virus neutralisation differs among pestiviruses. Using neutralising M A B ' s ,
Wensvoort and co-workers (unpublished observations) have identified three antigenic
domains with a total of eight epitopes on the major glycoprotein of H C V . Three
additional domains on the same glycoprotein comprising five epitopes were not
involved in neutralisation. Extending the results of Bolin et al. (5) by using 47 pesti­
viruses in competitive binding studies, Mateo and Moennig (unpublished observations)
identified ten epitopes on gp53 of BVDV relevant for neutralisation. Eight of them
were clustered in one domain, whereas one epitope - which so far could be identified
only on the homologous virus - was located outside this domain. In these studies,
binding of a single M A B was sufficient for virus neutralisation. However, a synergistic
effect of M A B ' s directed against different domains was observed with H C V
(Wensvoort, unpublished observations); in contrast, there was no such effect with
anti-gp53 M A B ' s of BVDV (Mateo and Moennig, unpublished observations).
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In 1987, a workshop was held at the Hanover Veterinary School (FRG) to compare
50 M A B ' s against 43 pestivirus isolates. Materials were contributed by thirteen
E u r o p e a n laboratories (38; tables summarising the data are provided u p o n request
by Prof. V. Moennig). It soon became clear that the ability of M A B ' s to discriminate
between antigenic variants was very powerful: numerous differences were found
among strains bearing the same n a m e b u t coming from different laboratories a n d
having distinct passage histories. These results emphasise the need for cautious
interpretation when comparing results obtained with the " s a m e " viruses in different
laboratories (38).
Interactions between BVDV and the host cell
All pestiviruses possess a similar host spectrum. BVDV naturally infects pigs,
sheep, goats a n d a wide range of wild ruminants whereas H C V is transmissible to
cattle and small ruminants (14, 18, 39, 40). T h e pestivirus host range for cultured
cells is even broader (23). However, despite their ability t o cross species barriers,
pestiviruses in general replicate inefficiently in heterologous hosts. In most cases they
cause neither cytopathology in culture n o r clinical disease. BVDV-induced disease
in sheep seems t o be an exception.
In Prof. Moennig's laboratory in Hanover, a M A B directed against a bovine cell
surface protein was shown to interfere specifically with the infectivity of a n u m b e r
of cpBVDV strains while leaving infection unimpaired with H C V a n d Border disease
virus, as well as with parainfluenza 3 virus and infectious bovine rhinotracheitis virus
(38). These findings suggest that a specific cell surface receptor mediates entry of
BVDV into bovine cells. F u r t h e r m o r e , it appears that different pestiviruses m a y n o t
share the same receptor, at least not in bovine cells. However, when studied more
closely using immunoperoxidase techniques, the inhibition of infection by the Hanover
M A B was not always complete; a few foci of infected cells were detectable in
monolayers pretreated with this M A B . Therefore, either multiple receptors for BVDV
m a y exist on cells or a less efficient, receptor-independent mechanism of virus
internalisation m a y be operative, as has been described for other viruses (35, 37).
The biological significance of receptor molecules for the histotropism of
pestiviruses is n o t yet understood. It has been shown that the receptor specificity of
viruses can be altered u p o n passage in cultured cells (50). T h e ability of pestiviruses
to adapt to heterologous hosts by expressing new attachment sites on the virion needs
to be investigated. T h u s , pestiviruses infecting bovine, ovine a n d porcine cells alike
have been identified, b u t so have strains infecting two or only one of the above species
(Moennig, unpublished observation). T h e variation may even be greater when wild
ruminants are t a k e n into account (18, 40).
The biotypes of BVDV
Cytopathogenicity of pestiviruses is a property which depends on genetic factors
of the virus as well as on the type of cell culture used (23). In general, H C V does
not produce cytopathology in porcine cell cultures; only a few exceptions have been
reported (19, 29). Border disease virus a n d BVDV strains behave differently with
respect to cytopathogenicity, and numerous cp isolates exist. The recent appreciation
of the significance of ncp and cp biotypes for the pathogenicity of BVDV has focussed
attention on the determinants of cytopathogenicity. T h e fact that pairs of ncp a n d
cpBVDV isolates from MD-affected animals are serologically indistinguishable (but
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distinct from other pairs) suggests that only minor alterations have occurred.
Comparison of the viral polypeptides of the two BVDV biotypes has indeed revealed
a difference: whereas cpBVDV isolates possess b o t h the p80 and p l 2 5 (amongst other
proteins), ncp viruses display only p l 2 5 ( 1 , 16, 45). Earlier peptide mapping data
have shown the p80 and p l 2 5 to be structurally related (48). More recently, the genetic
relationship between these polypeptides has been proven, and a 54kd protein related
t o p l 2 5 b u t unrelated to p80 has been identified (11). With this difference between
the cp and ncp biotypes of BVDV identified, questions arise concerning the function
of the p l 2 5 and its cleavage products p54 and p80, during viral replication and in
the origin of biotypes. It has been suggested that cp biotypes arise by m u t a t i o n from
ncpBVDV in persistently infected animals (27). It is tempting to speculate that a
mutation affecting a virus-encoded protease or a protein cleavage site might be
responsible for the conversion.
W h e n various unrelated BVDV field isolates were screened using M A B ' s directed
against the gp53 and gp48 envelope glycoproteins (for protein nomenclature see ref.
12), a wide spectrum of divergent reactivities was found that appeared independent
of the biotype. T h e same analysis, but now including pairs of cp and ncp viruses
isolated from fatal M D cases, showed a high degree of antigenic similarity within
a pair. This observation underlines the concept that cp biotypes of BVDV m a y arise
by mutation from ncp strains (13).
Mutations in envelope genes can be easily demonstrated. In collaboration with
the Regional Veterinary L a b o r a t o r y in G o u d a (The Netherlands) and the Institute
of Virology in Hanover, we have selected a panel of ten M A B ' s directed against four
domains and multiple subdomains of the gp53 (20, 44) and tested it against m o r e
t h a n 500 isolates of BVDV. Again, a wide variety of reactivities was seen, with every
conceivable combination of one to eight M A B ' s binding t o cell monolayers infected
with a given isolate. Interestingly, however, there were m a n y isolates in which a
peroxidase-linked antibody staining pattern indicative of mixed viral populations was
observed. Thus with a given isolate, one or several MAB's led to homogeneous staining
of the monolayer, whereas other M A B ' s stained only patches or single infected cells
(Kreeft and Horzinek, unpublished observations). Since the homogeneously stained
cultures establish the presence of BVDV in every cell, the anomalous antigen
distribution evidenced by some M A B ' s must b e interpreted in terms of emergence
of m u t a n t s which have acquired (or lost) the corresponding epitope.
THE OUTLOOK FOR PESTIVIROLOGY
The diagnosis of pestivirus infections is faced with several problems. Current
routine procedures are time-consuming and often inaccurate. Discrimination between
pestivirus strains by classical virological and serological means is difficult (8, 31).
However, all this is now expected to change as M A B ' s , nucleic acid probes and
synthetic peptides become available.
Broadly reactive M A B ' s to H C V are currently used in routine diagnostic
procedures for the differentiation of H C V and BVDV infections (21, 55). BVDVspecific M A B ' s offer the opportunity for development of an antigen-capture E L I S A .
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Such an assay will be valuable for the detection of persistently infected animals within
herds. Although yet to be explored, nucleic acid probes offer the potential for highly
specific and sensitive detection of virus directly in blood cells.
A problem of economic significance is the lack of simple procedures t o detect
antibodies against pestiviruses in field sera. Present serological techniques d o not
discriminate between antibodies produced in pigs after infection with H C V and BVDV.
Competition E L I S A procedures using M A B ' s as described by Juntti et al. (28) can
be implemented to approach this problem. Synthetic peptides reactive exclusively with
antibodies to specific pestiviruses offer another diagnostic possibility.
Understanding the pathogenesis of the M D syndrome is a major objective of future
work. The elucidation of the molecular differences between biotype pairs of BVD
viruses will be important in attaining this goal. Currently, two cp virus genomes (Osloss
and NADL) have been largely cloned and sequenced, and others will follow. However,
if we are t o gain insight into the cooperation between cytopathogenic and n o n cytopathogenic BVDV, it will be essential to analyse naturally occurring virus pairs
capable of inducing M D and identify the mutations relevant t o pathogenesis.
ACKNOWLEDGMENTS
The author should like to t h a n k M . S . Collett and V. Moennig for their
contributions to this chapter, m a n y of which have been included in a recent review
article on pestiviruses in general (12). The collaboration of H . Kreeft in screening
BVDV field isolates is gratefully acknowledged. T h a n k s are also due t o the authors
whose unpublished observations are mentioned in the text.
* *
INTRODUCTION SUR LE VIRUS DE LA DIARRHÉE VIRALE BOVINE. - M.C. Horzinek.
Résumé : Etant donné l'organisation du génome des pestivirus, telle qu'elle a
été récemment déterminée, il n'est plus possible de les classer dans la famille
des Togaviridae. A titre provisoire, il faudrait plutôt les considérer comme un
nouveau genre des Flaviviridae, indépendamment des différences dans les gènes
non structurels. Comme les autres virus à ARN positif, les pestivirus sont
extrêmement variables ; outre des mutations ponctuelles, des recombinaisons
peuvent favoriser leur comportement capricieux. Une caractéristique pouvant
être importante dans la pathogénie des infections par le virus de la diarrhée
virale bovine, est le fait qu'un biotype non cytopathogène peut devenir
cytopathogène. L'action conjointe des deux variantes chez un même animal,
produisant le tableau clinique grave connu sous le nom de «maladie des
muqueuses», est un cas unique en virologie ; l'élucidation de ce mécanisme peut
éclairer d'un jour nouveau la pathogénie d'autres maladies sporadiques dont
on soupçonne qu'elles sont dues à des virus.
MOTS-CLÉS : Anticorps monoclonaux - Biotypes - Flaviviridae - Maladie des
muqueuses - Pestivirus - Polypeptides - Taxonomie - Variation antigénique Virus de la diarrhée virale bovine.
*
* *
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INTRODUCCIÓN AL VIRUS DE LA DIARREA VIRAL BOVINA. - M.C. Horzinek.
Resumen: Dada la organización del genoma de los pestivirus tal como se ha
establecido recientemente, su clasificación como miembros de la familia
Togaviridae ya no es sostenible. Convendría, provisoriamente, considerarlos
más bien como un nuevo género de Flaviviridae, independientemente de las
diferencias en los genes no estructurales. Como ocurre con los demás virus de
ARN positivo, los pestivirus son extremadamente variables; además de las
mutaciones puntuales, las recombinaciones pueden favorecer su comportamiento
caprichoso. Una característica que puede ser importante en la patogenia de las
infecciones por virus de la diarrea viral bovina es que un biotipo no citopatógeno
puede hacerse citopatógeno. La acción conjunta de las dos variantes en un mismo
animal, que produce el cuadro clínico grave conocido como enfermedad mucosa,
es un caso único en virología; la elucidación de tal mecanismo puede contribuir
a aclarar la patogenia de otras enfermedades esporádicas que se sospecha
causadas por un virus.
P A L A B R A S CLAVE: Anticuerpos monoclonales - Biotipos - Enfermedad
mucosa - Flaviviridae - Pestivirus - Polipéptidos - Taxonomía - Variación
antigénica - Virus de la diarrea viral bovina.
*
* *
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