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Journal of Virology, November 2001, p. 10550-10556, Vol. 75, No. 21
Centre for Equine Virology, School of
Veterinary Science, The University of Melbourne, Parkville,
Victoria 3010,1 and St. Vincent's
Institute of Medical Research, Fitzroy, Victoria
3065,2 Australia
Received 27 February 2001/Accepted 31 July 2001
The nucleotide and deduced amino acid sequences of the P1 region of
the genomes of 10 independent equine rhinitis A virus (ERAV) isolates
were determined and found to be very closely related. A panel of seven
monoclonal antibodies to the prototype virus ERAV.393/76 that bound to
nonneutralization epitopes conserved among all 10 isolates was raised.
In serum neutralization assays, rabbit polyclonal sera and sera from
naturally and experimentally infected horses reacted in a consistent
and discriminating manner with the 10 isolates, which indicated the
existence of variation in the neutralization epitopes of these viruses.
Equine rhinitis A virus
(ERAV; formerly equine rhinovirus 1 [22, 23, 48]) was
recently renamed and reclassified in the genus Aphthovirus
of the family Picornaviridae (17) and is among many viruses that cause respiratory disease in horses worldwide. ERAV
is emerging as a serious pathogen of horses (4, 23), and
has also been shown previously to infect humans and other species
(3, 32, 34, 42). The isolation and characterization of
ERAV were first reported in the United Kingdom in 1962 (33). Subsequently, ERAV has been isolated from horses
worldwide (5, 12, 15; M. J. Studdert and L. J. Gleeson, Letter, Aust. Vet. J. 53:452, 1977). Most
isolations of equine rhinitis viruses have come from the nasopharynx of
horses with acute febrile respiratory disease. However, horses may
carry and shed virus in their urine and feces for up to 4 weeks
postinfection (28, 33). Seroepidemiologic studies indicate
that morbidity rates may reach 50%, particularly where older horses
are the majority of the population tested (3, 42).
Amino acid substitutions in picornavirus capsid proteins, particularly
in the surface loops of the capsid protein VP1, are responsible for the
antigenic variation seen between serotypes and strains (9, 20,
30). Antigenic variation has important implications in the
design of effective vaccines to control infection and reinfection and
also in the design of diagnostic tests able to detect all serotypes and
strains of these viruses. To understand the antigenic relationships
between different ERAV isolates, we have determined the nucleotide
sequences of the P1 region of 10 ERAV isolates from Australia, the
United Kingdom, Switzerland, and the United States (Table
1) and developed a panel of monoclonal and polyclonal antibodies to probe the antigenic relationships between
these viruses.
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.21.10550-10556.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Sequence Conservation and Antigenic Variation of
the Structural Proteins of Equine Rhinitis A Virus
ABSTRACT
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TABLE 1.
Origin and passage history of ERAV isolates used in the
study
The nucleotide sequence of the complete viral capsid protein coding
region (P1 region) was determined for 10 ERAV isolates, of which eight
sequences were previously unknown (967/90, 360007, 544/82, 4066/79,
V1722/70, P200/75, P346/75, and P1316/92). The nucleotide sequence of
ERAV.PERV/62 contained five nucleotides that differed from the
published sequence (48), and there were 14 nucleotide
differences between the ERAV.393/76 sequence obtained for this study
and the original published sequence (22). Considerable variability was found at the nucleotide level, with identities ranging
between 79.6 and 96.6% among the 10 isolates (data not shown), where
many of the sequence differences are in the third codon position and as
such do not result in many amino acid changes (Fig.
1). The amino acid identity and
similarity ranged from 96.8 to 99.3% and 98.4 to
99.7%, respectively, among the 10 isolates. Within sites that were
variable, most of the differences represent conservative amino acid
substitutions, which is analogous to accumulation of amino acid
substitutions in foot-and-mouth disease virus (FMDV) (25,
26). ERAV.393/76, however, differs in several amino acids that
are completely conserved in all other isolates. This might reflect a
higher degree of adaptation to cell culture than is the case for all of
the other, less passaged isolates (7, 14, 41).
Phylogenetic trees for the 10 ERAV isolates representing the entire P1
region showed these isolates to be clustered closely into six main
branches. Dendrograms were similar for both P1 (Fig. 2A) and VP1 (data not
shown). The ERAV isolates formed a closely related cluster as a branch
of the Aphthovirus genus as previously described (Fig. 2B)
(22, 48). The branch lengths between the ERAV isolates are
shorter than those between the FMDV serotypes, which is consistent with
the view that these ERAV isolates represent a single serotype.
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-helices and
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In order to understand the relationship of sequence changes to the
antigenic sites of ERAV, a panel of monoclonal antibodies (MAbs) was
prepared against the prototype isolate ERAV.393/76. Lymphocytes were
taken either from the inguinal and popliteal lymph nodes of mice that
were immunized with purified UV-inactivated ERAV.393/76
(11) emulsified in complete Freund's adjuvant or from the
spleens of mice that had received two further boosts of purified virus.
Lymphocytes from the spleen and the lymph nodes were used
separately in hybridoma fusions with Sp2/O-Ag14 myeloma cells as
described previously (19). Hybridomas were screened in
an enzyme-linked immunosorbent assay (ELISA) comprising
plates coated with purified ERAV.393/76 and reactive hybridomas
cloned twice by limiting dilution. The specificities of these MAbs were determined by Western blotting against ERAV.393/76 (data not shown), and the properties of these MAbs are summarized in Table
2. Of the seven MAbs, four recognized the
VP2 protein, one recognized VP1, and one recognized VP3. The seventh
MAb (L2G3) did not bind in Western blotting but was able to
immunoprecipitate [35S]methionine-labeled viral capsid
proteins and may therefore recognize a conformation-dependent epitope.
None of the MAbs was able to neutralize virus infectivity, while most
of the MAbs bound in immunofluorescence assays to six different ERAV
isolates, suggesting conservation of the nonneutralization epitopes
between these viruses. The epitopes of these MAbs were more precisely
mapped using an ERAV.393/76 P1 gene-specific phage display library
(40) and were further defined with a panel of glutathione
S-transferase fusion proteins displaying parts of the
isolated phagotopes. All the MAb epitopes identified represent segments
of sequence compatible with their reactivity against viral proteins in
Western blotting (Table 2 and data not shown). Furthermore, these
epitopes were conserved among all 10 isolates (Fig. 1), and this
explains their ability to bind to each of the representative isolates
by immunofluorescence.
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The relationships among isolates were also examined using serum
neutralization assays with ERAV polyclonal sera raised either in
rabbits or experimentally and naturally in horses (11).
Consistent results were obtained in two independent experiments, and
the results from one of these experiments are shown in Fig.
3. The experimentally infected horse and
rabbit sera showed the highest neutralizing antibody titers to the
prototype ERAV.393/76 isolate with which they were infected or
inoculated, and these antisera neutralized each of the other isolates
to various degrees. In particular, each serum had a consistent and
significantly (
10-fold) lower neutralizing antibody titer against
PERV/62 (Fig. 3). Isolate P346/75 had a two- to sixfold-lower
neutralizing antibody titer than that of isolate 393/76 depending on
the sera tested, and isolate 544/82 showed a significantly (4-fold)
lower neutralization titer than did isolate 393/76 with the polyclonal
horse sera but not with the polyclonal rabbit serum. Isolate P1316/92
showed similar neutralizing antibody titers to 393/76 against all sera except SM, which was obtained from a horse naturally infected with ERAV
(23). Isolates 360007, 4066/79, 967/90, V1722/75, and
P200/75 were neutralized to similar levels as ERAV.393/76 by each of
the sera tested. Therefore, despite the high levels of sequence
conservation, some antigenic variation in neutralization epitopes of
the viruses could be demonstrated.
|
25%, therefore, show a neutralization titer significantly
reduced from that of the that serum against 393/76. The ERAV
isolates 393/76, 360007, 4066/79, 967/90, P1316/92, V1722/70, P346/75,
P200/75, 544/82, and PERV/62 (left to right; respectively) were
tested in serum neutralization assays with horse and rabbit sera. Horse
sera G, S, and Sk and rabbit sera were from animals experimentally
infected with ERAV.393/76 (The three-dimensional crystal structure of many picornaviruses has
shown that major differences between picornavirus serotypes are
concentrated within the surface-exposed loops of the virus capsid
proteins (9, 16, 20, 21, 30). Amino acid variation within
these loops alters the antigenic properties of the viruses and is
responsible for the diversity of virus serotypes (27). Picornavirus capsid proteins share a great deal of structural homology,
where VP1, VP2, and VP3 are each composed of eight-stranded 
-barrels
and differ in the size and conformation of the connecting loops between
the strands and the extensions of their amino and carboxyl termini
(37). Alignment of the predicted secondary structural
elements of the ERAV capsid proteins with those of FMDV and other
picornaviruses of known three-dimensional structure (2, 24,
36) suggests the location of loop and beta-sheet regions for the
ERAV capsid (Fig. 1) (48). These alignments predict that
ERAV VP1 contains longer connecting loops between -barrel structures
than does FMDV, with the exception of the G-H loop. The long
G-H loop of FMDV contains the integrin-binding motif RGD and is
the major epitope to which neutralizing antibodies are directed
(6, 10, 27, 45-47). Four other antigenic sites of FMDV
serotype O are also located across the P1 region (18). The
G-H loop of ERAV is much smaller than that of FMDV and has no
identifiable integrin-binding motif. Among the 10 ERAV isolates, amino
acid variation appears to occur mostly in proposed loop regions of the
capsid proteins, particularly in the A2-B loop of VP2
between amino acids 110 and 134 and the E-F loop in VP1 corresponding to amino acids 645 to 676 (Fig. 1).
The epitopes of three MAbs localized to proposed loop or C-terminal regions of the capsid proteins. The MAbs detected mostly linear epitopes across the P1 region (L5G12 and L4E4 to VP2, L4G4 to VP3, and L7E8 to VP1), although no MAbs were generated to the smallest (4-kDa) capsid protein, VP4. One MAb, L2G3, appeared to bind to a conformation-dependent epitope, since this MAb bound well to whole virus in the ELISA and immunoprecipitation assay (data not shown) but did not bind to virus that had been fixed for immunofluorescence or reduced and denatured for Western blotting. The MAb epitopes identified by phage display mapped to regions of the VP2, VP3, and VP1 capsid proteins that were conserved across all 10 isolates. Conservation of the P1 amino acid sequences would predict that these viruses have a very close antigenic relationship, since the amino acid substitutions observed are mostly conservative and are dispersed randomly across the P1 region. The inability of these MAbs to neutralize virus infectivity and the conserved nature of these epitopes across the 10 ERAV isolates suggest that these regions are not subject to antibody-mediated selective pressures. Neutralizing MAbs were not obtained in successive fusions despite the presence of neutralizing antibodies in the serum obtained from these mice. This may be a reflection of bias introduced by selecting MAbs able to bind in ELISA, since virus bound to ELISA wells may have neutralization epitopes altered or unavailable for binding.
Antigenic sites of picornaviruses FMDV, poliovirus (PV), and human
rhinovirus have been well characterized. Although FMDV differs markedly
in the surface design from PV and human rhinovirus 14 (HRV14)
(2), the antigenic sites of all three appear to localize to regions in and around their receptor-binding sites (44). FMDV serotype O has five recognized neutralization
epitopes-antigenic sites across the P1 region (18).
Site A was the first major epitope identified, located within the
G-H loop of VP1 and encompassing the RGD integrin-binding motif
(1, 21). PV and HRV14 each contain three major antigenic
sites (13, 29, 31, 38, 39), which are highly variable and
consist of surface loops surrounding the receptor-binding canyon on the
surface of the virion (35). Despite the highly conserved
amino acid sequence among the 10 ERAV isolates, polyclonal serum
neutralization data suggest that some variation does exist between
neutralization epitopes of ERAVs. PERV/62 was significantly different
from the 393/76-like viruses based on the neutralizing antibody titers
of polyclonal sera. PERV/62 is the earliest ERAV isolate used in this
study. The amino acid differences of viruses isolated at later times
may represent evidence of selective immunologic pressure or replication
biases that have altered the antigenic structure of viruses over time, in order to escape neutralization by circulating antibodies to earlier
isolates. The ERAVs isolated subsequent to PERV/62 show higher
cross-neutralizing antibody titers to the polyclonal sera. The location
of individual amino acid substitutions between ERAV isolates that may
explain the variable neutralization results between ERAV isolates is
not obvious. As with FMDV and other picornaviruses, amino acid
substitutions across a number of regions may alter the capacity of
antibodies to bind and neutralize ERAV. Elucidation of the
neutralization epitopes of ERAV by selection of escape mutants
resistant to neutralization or by mapping epitopes of neutralizing MAbs
is necessary in order to more precisely define the critical amino acids
involved for ERAVs. Although ERAVs are not as divergent as the FMDV
serotypes, variation in the neutralization epitopes of ERAV isolates
raises the possibility that a horse could be susceptible to multiple
ERAV infections over a lifetime, since infection with a PERV/62-like
isolate may not afford protection from a 393/76-like virus.
Furthermore, the variation also has important implications for the
design of effective vaccines that are able to protect against infection
with all possible ERAV isolates.
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ACKNOWLEDGMENTS |
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We thank Dorothy Holmes, Edward Dubovi, and Randall Renshaw, Cornell University, and Marianne Weiss, The University of Berne, for providing many of the ERAV isolates.
This work was supported by Racing Victoria and a Special Virology Fund. A.V. was a recipient of an Australian Postgraduate Award (Industry) scholarship with Racing Victoria as the industry partner.
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FOOTNOTES |
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* Corresponding author. Mailing address: Centre for Equine Virology, School of Veterinary Science, The University of Melbourne, Park Dr. and Flemington Rd., Parkville, Victoria 3010, Australia. Phone: 61 3 8344 7375. Fax: 61 3 8344 7374. E-mail: carolah{at}unimelb.edu.au.
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Journal of Virology, November 2001, p. 10550-10556, Vol. 75, No. 21
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.21.10550-10556.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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[Abstract] [Full Text] -
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