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Journal of Virology, July 2000, p. 6178-6185, Vol. 74, No. 13
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Variability and Immunogenicity of Caprine
Arthritis-Encephalitis Virus Surface Glycoprotein
S.
Valas,1,*
C.
Benoit,1
C.
Baudry,1
G.
Perrin,1 and
R.
Z.
Mamoun2
AFSSA-Niort, Laboratoire de Recherches
Caprines, F-79012 Niort Cedex,1 and
Laboratoire Rétrovirus et Thérapie, INSERM U443,
Université Victor Segalen Bordeaux 2, F-33076 Bordeaux
Cedex,2 France
Received 3 February 2000/Accepted 29 March 2000
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ABSTRACT |
The complete surface glycoprotein (SU) nucleotide sequences of
three French isolates of caprine arthritis-encephalitis virus (CAEV)
were determined and compared with those of previously described isolates: three American isolates and one French isolate. Phylogenetic analyses revealed the existence of four distinct and roughly
equidistant evolutionary CAEV subtypes. Four conserved and five
variable domains were identified in the SU. The fine specificities of
antibodies produced against these domains during natural infection were
examined using a pepscan analysis. Nine immunogenic segments were
delineated throughout the conserved and variable domains of SU, two of
them corresponding to conserved immunodominant epitopes. Antigenic determinants which may be involved in the immunopathogenic process induced by CAEV were identified. These results also provide sensitive and specific antigen peptides for the serological detection and differentiation of CAEV and visna/maedi virus infections.
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TEXT |
The surface glycoprotein (SU) of
lentiviruses contains determinants important for cellular host range,
infectivity, cytopathogenicity, and disease progression. The region of
the envelope gene encoding the SU displays a particularly high level of
sequence variation, resulting in hypervariable domains interspersed
with less variable domains throughout the protein. Both variable and
conserved domains are major targets for the host immune response,
including virus-neutralizing antibodies and cell-mediated cytotoxicity.
Therefore, SU has been an obvious candidate in vaccine trials and
diagnostic assays of infection by lentiviruses, such as human, simian,
and feline immunodeficiency viruses (HIV, SIV, and FIV, respectively)
(for reviews, see references 10, 19, 33, 34, and
38).
Caprine arthritis-encephalitis virus (CAEV) is a lentivirus causing
slow and persistent inflammatory diseases in goats, primarily arthritis
and mastitis (9, 42). These inflammatory diseases are the
result of viral infection of cells of monocyte/macrophage lineage,
which are the main target cells in vivo (13, 43, 44). The
results of a recent experiment using live attenuated CAEV vaccine in
goats have demonstrated the development of some protection against
challenge with the pathogenic homologous virus (17),
indicating the effectiveness of an immunological control of virus
replication. However, this protective immunity did not prevent the
development of clinical signs of disease, although the lesions were not
as severe as those found in wild-type CAEV-infected goats. Previous
investigations have indicated that the presence and severity of
arthritic lesions are specifically correlated with the predominant
humoral immune response directed against the SU and transmembrane (TM)
CAEV envelope glycoproteins (3, 22, 30, 35). Collateral
experiments have demonstrated that infected goats having early dominant
anti-SU antibody responses (48) as well as goats challenged
with CAEV during persistent CAEV infection or after vaccination with
inactivated virus (37) developed more rapidly
progressing and severe arthritis. Conversely, long-term infected
nonprogressor goats are characterized by a lack of clinical pathology
and by low anti-CAEV antibody titers, compared to arthritic goats
(30, 48). These observations suggest that antigenic
determinants of envelope glycoproteins of CAEV may be involved in the
immunopathogenic process leading to inflammatory diseases.
Precise knowledge of the immunogenic domains of CAEV glycoproteins
would provide useful information on the antigenic structures to be
included in candidate vaccines. Four immunodominant epitopes have been
identified in the TM ectodomain of CAEV (3). Three of them
have been shown to be associated with clinical arthritis. In contrast,
the immunogenic epitopes of the SU are still unknown. Our objective is
to provide the basic framework for understanding the CAEV-induced
pathogenic process and for vaccine development. In this study, we have
defined the variability profile of the SU, and we have precisely mapped
epitopes within conserved and variable domains which elicit humoral
immune responses during natural CAEV infection.
Variability of CAEV SU.
At present, the complete SU nucleotide
sequences (29, 50, 61, 62) of only one French (strain 680)
and three American (strains Cork, 63, and 1244) CAEV isolates have been
analyzed. Expanded surveys of CAEV isolates are required to explore the extent and nature of SU diversity. In the present study, the complete SU nucleotide sequences of three new French CAEV isolates (named 021, 032, and 786) selected for their relative great divergence with the
prototype Cork and 680 strains using heteroduplex mobility assay
(61; unpublished data) were determined. Genomic DNAs
were purified (Isoquick; Microprobe) from explanted goat synovial
membrane cells (strain 786) or cocultures of milk mononuclear cells
with goat synovial membrane cells (strains 021 and 032) harvested at maximum cytopathic effects. One microgram of DNA was subjected to 35 cycles of PCR amplification using oligonucleotide primers 5084 and 5087 as previously described (61), and the resulting 2.2-kb PCR
products containing the entire SU sequences were cloned into pGEM-1
vector. For each strain, three independent rounds of PCR and cloning
were done, and at least three clones were sequenced and aligned to
determine a consensus sequence and rule out PCR artifacts or
intrastrain variability. To provide information about the evolutionary
relationships of these newly identified French CAEV isolates with
previously reported prototype CAEV isolates, a phylogenetic tree was
constructed from the full-length SU coding sequence (1.6 kb). In
addition, three previously published prototype SU sequences (strains
K1514, EV-1, and SAOMVV) (49, 52, 58) of visna/maedi virus
(MVV), an ovine lentivirus antigenically and genetically closely
related to CAEV (14, 65), were also included. Phylogenetic
relationships were determined by using the neighbor-joining algorithm
with the Kimura two-parameter distance matrix (PHYLIP) (11).
Sites at which there was a gap in any of the aligned sequences
were excluded from all comparisons. To evaluate the consistency of
the phylogenetic groupings, branching order reliability was evaluated
by 1,000 replications of bootstrap resampling analysis. As shown in
Fig. 1, all CAEV isolates form a related
group on a clearly separate branch from the MVV group. Since previous
phylogenetic studies using short nucleotide sequences have reported the
existence of French ovine lentiviruses that were more closely related
to CAEV than to the prototype MVV strains (32), phylogenetic
trees were also constructed using different small regions of the SU
coding sequence. These analyses yielded virtually identical trees,
confirming the existence of a distinct CAEV cluster and ruling out
possible recombination events. Genetic distances between CAEV and MVV
SU sequences were estimated by means of the CLUSTAL W program (Table
1) (60). The intergroup Hamming distances of amino acid sequences ranged from 29.2 to 36.7%,
indicating that a large distance exists between CAEV isolates and
prototype MVV isolates. Phylogenetic relationships among CAEV isolates
revealed the existence of a cluster of four distinct subtypes; one of
these harbored exclusively American isolates, while the three others
represented French subtypes with nearly 12% genetic diversity between
each pair of subtypes. The intragroup distances of amino acid sequences
ranged from 7.8 to 20.1% in the CAEV group. The amino acid distances
were 14.9 to 20.1% between French and American CAEV isolates and 7.8 to 15.7% among the four French isolates, confirming that French
isolates distinctly differ from the American isolates and have evolved
in different but closely related subtypes.
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FIG. 1.
Phylogenetic relationships of French CAEV isolates to
prototype CAEV and MVV strains. The SU multiple sequence alignment was
resampled by the bootstrap method (1,000 data sets); an unrooted tree
generated by neighbor-joining analysis is shown. The horizontal and
vertical orientations of branches are noninformative and for clarity
only; branching patterns and branch lengths reflect phylogenetic
distance relationships. The numbers on the nodes represent the
percentage of bootstrap samples.
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The amino acid sequence alignment of all CAEV SU precursor sequences
(four French and three American isolates) is shown in
Fig.
2. A hypervariability was observed for
the large leader peptide,
including insertions and deletions. The three
French isolates
(021, 032, and 786) characterized in this study
exhibited an intact
open reading frame without unusual insertions or
deletions, resulting
in a length of 548 ± 2 amino acids for the
mature SU. The 2-amino-acid
length variation among French SU sequences
corresponded to a single
deletion located at the carboxy terminus of SU
of the first reported
French CAEV isolate (strain 680). This deletion
allowed the loss
of one of the two potential cleavage sites between the
SU and
TM of the strain 680, while these two sites were well conserved
in the three newly described French isolates. A perfect conservation
of
the 22 cysteine residues in the SU was observed among all isolates.
Of
the 24 potential N-linked glycosylation sites, 17 (71%) were
conserved
and, curiously, 30% of the cysteine residues were located
within or
just beside these conserved N-linked glycosylation sites.
Five variable
regions (V1 to V5) and four conserved regions (C1
to C4) were
identified. The relative distribution of these variable
and conserved
domains of the mature SU is presented in Fig.
3,
which illustrates the variability
profile of SU based on the frequency
of amino acid substitutions
relative to the consensus sequence
and smoothed using a 10-amino-acid
window size. The first conserved
region (C1) spanning 86 amino acids
corresponded to the amino
terminus of SU. This region was followed by
two contiguous short
hypervariable regions (V1 and V2). The V1 region
was consistently
the most variable but contained a perfectly conserved
potential
N-linked glycosylation site (position 182). The V2 region was
flanked by two stretches of conserved amino acids, particularly
cysteine residues. The C3 region spanning 81 residues (positions
393 to
474) in the central part of the mature SU was highly conserved,
with
80% conservation among all isolates. This C3 region, together
with the
neighboring V4 region, contains the majority of the conserved
N-linked
glycosylation sites (11 of 17) and cysteine residues
(10 of 22),
suggesting that they form a highly constrained and
surface-exposed
domain. It had been proposed that the V4 region
of CAEV and MVV may be
analogous to the V3 principal neutralizing
domain of HIV-type 1 (HIV-1)
(
29,
57). The V5 region located
at the carboxy terminus
overlaps the first of the two putative
SU-TM cleavage sites.
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FIG. 2.
Alignment of predicted SU precursor amino acid sequences
of CAEV isolates. The sequences were aligned with a consensus sequence
(Cons) consisting of the most frequent residue at a given position.
Dashes in the sequence alignment represent deletions. Variable domains
(V1 to V5) are delineated by overlines. *, conserved cysteine
residue; ---, conserved potential N-linked
glycosylation site.
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FIG. 3.
Relationships between immunogenicity and variability
profiles of CAEV SU. Variable and conserved domains of the SU were
established from all available sequences (those for three American and
four French isolates). The variability profile is based on the
frequency of amino acid substitutions relative to the consensus
sequence and smoothed using a 10-amino-acid window size. The amino acid
numbers on the x axis start with the mature SU
amino-terminal Glu as residue 1 (29). The immunogenic sites
identified in this study are delineated by hatched areas. Below the
variability profile, the conserved regions are shown as white boxes and
the variable regions are shown as black boxes. Stick with circle,
conserved potential N-linked glycosylation site; arrowhead, conserved
cysteine residue.
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Immunogenicity of CAEV SU.
To precisely map linear epitopes in
the CAEV SU glycoprotein which elicit humoral immune responses during
natural infection, a pepscan analysis was performed using 77 synthetic
peptides. Overlapping peptides were constructed to cover the entire
amino acid sequence of the mature SU of the French CAEV strain 680 (Table 2). The peptides were designed to
be 14 amino acids long and to overlap each other by 7 amino acids. The
residues for each peptide were numbered relatively to the known amino
terminal Glu1 of the mature SU, corresponding to the
Glu87 of the envelope precursor (29). The
peptides were synthetized by automated 9-fluorenylmethyloxycarbonyl
chemistry (Chiron Mimotopes Peptide Systems, Clayton, Australia)
(4). An amino-terminal biotinylated tetrapeptide
(Ser-Gly-Ser-Gly) was added to all peptides to facilitate epitope
accessibility and absorption to streptavidin-coated wells. Fifty-five
immune sera were collected from naturally infected goats originating
from different flocks in France. All infected animals were PCR positive
and seropositive when tested by commercially available enzyme-linked
immunosorbent assays (ELISAs) employing whole-virus preparations as
antigens (Chekit CAEV/MVV; Behring). Serum samples were tested at a
dilution of 1:100 against each peptide in a standard ELISA according to
the manufacturer's instructions, and optical densities were recorded
on an automatic ELISA plate reader (Labsystem) at 405 nm. The cutoff
level for positivity for each peptide was defined as the mean
absorbance value of a panel of 32 negative control sera plus 3 standard
deviations. As shown in Table 2, a wide range of peptide
immunoreactivities (0 to 84%) was observed. Seventeen immunoreactive
peptides (P1, P6, P28, P32, P53, P54, P56, P58, P59, P60, P64, P66,
P68, P74, P75, P76, and P77), defined by 
20% positive reactivity
with goat immune sera, were identified. By correlating the relative
reactivities of immunoreactive peptides with adjacent or overlapping
peptides, nine major immunogenic segments were identified in the SU
(Table 2; Fig. 3). These have been tentatively assigned to the regions of amino acids Glu1-Ser14,
Cys36-Tyr49,
Asn190-Gly203,
Lys218-Lys231,
Gly365-Ser378,
Asn386-Gln399,
Met407-Glu427,
Val442-Arg483, and
Val512-Leu539. The most immunoreactive peptides
(P1, P74, P75, and P76), i.e., the immunodominant peptides, recognized
by at least 58% of immune sera, were located exclusively at the amino
(residues 1 to 14) and carboxy (residues 512 to 539) termini of the SU.
The amino-terminal peptide (P1, residues 1 to 14) of SU reacted with
67% of the goat immune sera tested. Immune serum reactivity fell to
2% with peptide P2 (residues 8 to 21), delineating the immunodominant
amino-terminal epitope to the first 14 amino acids of mature SU. The
immunodominant peptide P75 (residues 519 to 532) located at the carboxy
terminus of SU displayed the strongest relative reactivity of all
peptides tested, exhibiting 84% serological reactivity with the goat
immune sera. The comparison between the reactivity of peptide P75 with those of the two overlapping immunoreactive peptides P74 and P76 suggests that there may be at least two major linear epitopes in the
region encompassing residues 519 to 532. In addition, the level of
immunoreactivities (absorbance/cutoff ratio) of positive immune sera to
immunoreactive peptides (Fig. 4) revealed
that immunodominant peptides P1 and P75 were strongly recognized by the
majority of sera tested. Using a combination of only five immunoreactive peptides (P28, P64, P74, P75, and P76) the sensitivity increased to 96.4%, indicating that the development of an ELISA based
on such peptides would give a highly sensitive and specific test for
the detection of CAEV infection. The relationships between localization
of the immunogenic peptide determinants and the variability profile of
CAEV SU are illustrated in Fig. 3. As expected, all conserved regions
(C1 to C4) contained immunoreactive linear B epitopes. No
group-specific epitopes were identified within the V1 and V2
hypervariable regions and the less-variable V3 region. The V4 region
showed clearly different immunogenic patterns: 7 out of 17 (40%)
immunoreactive peptides described above were distributed throughout the
V4 region. Remarkably, a high concentration of conserved cysteine
residues and N-linked glycosylation sites was also found within this
region, suggesting that these immunogenic determinants are well-exposed
in the native protein structure. Despite a high degree of variability,
the short V5 region located at the carboxy terminus of SU contained one
of the two immunodominant epitopes included in peptide P75, suggesting
that the sequences of field isolates from which immune sera were
randomly collected were closely related to that of the prototype CAEV
680 used as a basis for peptide synthesis. Indeed, examination of amino
acid sequences in the V5 region (Fig. 2) revealed a high sequence
homology among French isolates, compared to the great divergence
observed between French and American isolates.
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FIG. 4.
Reactivity profiles of ELISA-positive immune sera to
immunogenic CAEV SU synthetic peptides. Each graph represents ELISA
reactivities to one peptide or to different peptides as indicated. Each
bar in the different serum reactivity profiles represents the ELISA
reactivity (absorbance value/cutoff [A405/C.O.]) of one
positive immune serum to an individual peptide. The number of positive
immune sera to an individual immunodominant peptide or to combined
immunoreactive peptides is indicated below each panel.
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In summary, results from combined analyses of variability and
immunogenicity of CAEV SU have revealed significant structural
similarities between the SU of CAEV and other lentiviruses, despite
the
lack of substantial sequence homology. Comparison of the SU
variation
profile of CAEV with that of HIV-1 (
40,
59) revealed
that
analogous conserved and variable domains exist between the
respective
SU glycoproteins of the two lentiviruses. Five variable
regions and
four conserved regions were identified in the CAEV
SU. We found that
conserved C1 (peptide 1) and C4 (peptide 74)
regions located at the
amino and carboxy termini, respectively,
of CAEV SU contain
immunodominant determinants displaying 67%
reactivity with immune sera
from natural infections. Examination
of caprine humoral immune
reactivities allowed the identification
of a distinct immunodominant
epitope (peptide 75, residues 526
to 532) in the carboxy terminus of
SU, located in the V5 region
just downstream from the immunodominant
epitope (residues 519
to 525) of the C4 region. This epitope reacted
with 84% of caprine
immune sera tested. Comparison of amino acid
sequences in the
V5 region revealed a high sequence homology among
French isolates
whereas sequences greatly differed between American and
French
isolates, suggesting that this immunogenic determinant is
conserved
between geographically linked CAEV isolates, a situation
reinforced
by extensive commercial exchanges of infected animals among
neighboring
regions. This is further supported by the inability of
immune
sera from goats experimentally infected by the American Cork
strain
to react with peptides P75 and P76 (data not
shown).
As for the HIV-1 SU, the first conserved region of CAEV SU was followed
by two contiguous hypervariable regions, V1 and V2.
These variable
domains and the V3 region do not contain group-specific
epitopes, as is
also the case for the analogous regions of HIV-1
SU (
41,
45), which are the targets of type-specific neutralizing
antibodies (
12,
15,
39,
45). The large V4 variable region
of
CAEV SU shows several striking features. Firstly, most of the
antigenic
determinants identified in this study are located within
this region.
Secondly, the glycosylation pattern of CAEV SU is
not uniformly
distributed but mapped essentially in the C3-V4
region, which also
contains a high concentration of conserved
cysteine residues. Finally,
the V4 region of CAEV SU is in an
analogous position to the V4-V5
region of SIV and FIV (
47),
which are the major targets of
neutralizing antibodies (
21,
55). In the case of these two
lentiviruses, amino acid mutations
in these regions of envelope protein
allow the virus to escape
from neutralization (
27,
56).
Recently, a type-specific discontinuous
neutralization epitope has been
identified in the V4 region of
MVV SU (
57). The
neutralization phenotype was found to map within
39 amino acids
corresponding to the immunogenic region encompassing
peptides 64 to 68 (residues 442 to 483) in the V4 region of CAEV
SU. Taken together,
these observations suggest that the V4 region
of CAEV SU is a highly
conformational and well-exposed immunogenic
domain which could be
involved in the emergence of neutralization
escape variants.
Furthermore, it has been shown that the extensive
glycosylation of CAEV
SU, which accounts for nearly 50% of the
total molecular weight of the
protein, contributes to the inaccessibility
of the SU epitopes to
neutralizing antibodies (
20). This may
explain, at least in
part, the apparent low neutralizing antibody
titers developed by some
CAEV-infected goats (
7,
8,
36).
In contrast, sheep infected
by MVV develop relatively high neutralizing
antibody titers against SU
epitopes. Interestingly, one of two
perfectly conserved N-linked
glycosylation sites in CAEV sequences
(amino acids 533 and 540 in Fig.
2) is missing in the equivalent
MVV region containing the major
neutralization epitope (
57),
suggesting that conservation of
a relatively high number of N-linked
glycosylation sites in the V4
region of CAEV SU would allow the
virus to escape the host neutralizing
immune
response.
Using a pepscan analysis, several studies have demonstrated that the
terminal ends of SU glycoproteins of HIV-1 (
16,
46)
and
equine infectious anemia virus (
1) also contain highly
conserved, immunodominant linear B epitopes. It appears that
extremities
of these lentiviral SU glycoproteins are exposed and
immunogenic
in their native state. We have found that peptide 1 and
particularly
peptide 75 exhibited a much higher level of serological
reactivity
than did all of the other CAEV SU peptides tested. In the
CAEV
infection model, the results of several studies have demonstrated
a direct correlation between the level of anti-Env antibodies
and the
development of arthritic lesions (
3,
22,
30,
35),
together
with high virus loads in synovial tissue of CAEV-infected
goats
(
8,
25,
28). Particularly, increased anti-CAEV SU
antibody
titers and a dominant population of SU-reactive T-helper
2-like
lymphocytes are associated with disease progression (
6,
48,
64). In vaccine experiments, immunization with inactivated
CAEV
resulted in exacerbation of arthritic lesions after in vivo
challenge
(
37). This concern has been described after immunization
with viral envelope glycoprotein subunit vaccines in other lentiviral
vaccine models such as SIV, FIV, and equine infectious anemia
virus
(
53,
54,
63). Finally, an enhancement of viral binding
and
entry into macrophages, the principal target cells in vivo,
have been
observed in vitro by using nonneutralizing antibodies
to CAEV
(
23). These observations, together with our results,
suggest
that conserved immunodominant epitopes located at both
amino and
carboxy termini of CAEV SU may contribute to the enhancement
of virus
replication and disease. The localization of one of the
main
immunodominant domains (P75), about 10 amino acids upstream
from the
SU-TM cleavage site, seems very intriguing. A parallel
can be
established between this situation and the role of a glycosylation
site
located about 10 amino acids upstream from the influenza
virus
hemagglutinin cleavage site; it has been reported that hemagglutinin
cleavability and influenza virus virulence are directly related
to the
nature of the sequence at this site (
18,
26). It could
be
proposed that in CAEV-infected goats, the level of recognition
of the
immunodominant site by antibodies would have a direct effect
on the
SU-TM cleavability and consequently on CAEV virulence and
pathogenicity. Further analyses would be necessary to evaluate
the role
of the immune response against this immunodominant site
during the
course of natural CAEV
infection.
As previously mentioned, a dominant humoral immune response to viral
envelope glycoproteins is a general feature of CAEV infection.
In
addition, experimental infection studies have revealed a characteristic
evolution of antibody responses towards CAEV antigens during the
course
of viral infection (
3). Sera of infected goats recognized
both SU and Gag proteins during the first weeks postinfection,
and then
anti-Gag antibody titers decreased slowly whereas anti-TM
antibodies
appeared much later. In contrast, anti-SU antibodies
were maintained
over time. Similar kinetics of antibody responses
have been observed in
experimentally MVV-infected sheep (
24).
Thus, SU appears to
be an obvious candidate for diagnostic assays
of CAEV infection. Our
results revealed the existence of conserved
immunodominant epitopes in
the SU which could be used as potential
diagnostic peptide antigens. No
individual peptide was reactive
with all of the CAEV-infected goat sera
tested, with the highest
sensitivity being 84%. However, the
combination of only five peptides
improved the sensitivity of CAEV
antibody detection, raising it
to 96.4%. In addition, the overall
divergence between CAEV isolates
of distant geographical regions did
not exceed 20%, which is approximately
2.5 times lower than that
observed for HIV-1 isolates (
31),
and would not drastically
impede serological diagnostic tests.
Finally, CAEV and MVV are closely
related viruses having >60%
amino acid homology and antigenically
cross-reactive structural
proteins (
14,
50). Earlier
experimental evidence, demonstrating
that sheep can be infected with
CAEV and that goats can be infected
with MVV (
2), has
supported the possibility of cross-species
transmission. More recently,
phylogenetic analyses from partial
nucleotide sequences of
pol and/or
env genes of European and American
ovine lentiviruses have led to the suggestion that these ovine
isolates
may have originated from a CAEV-like virus (
5,
32,
66).
Therefore, the inability of current serological methods
to
differentiate between the two small ruminant lentiviruses (SRLVs)
has markedly limited the interpretation of results obtained in
seroepidemiological studies (
51). Our results on diversity
and
immunogenicity of CAEV SU provide potential peptide substrates
for
the design of not only group-specific serological tests but
also
group-cross-reactive assays. The immunodominant epitope located
at the
amino terminus of CAEV SU (amino acids 1 to 14) that differs
by 50% in
amino acid sequence from MVV SU, would be used as a
group-specific
antigen. In contrast, the immunodominant epitope
located at the carboxy
terminus of the protein (amino acids 512
to 525) that differs by only
one amino acid substitution between
the two viruses could be used for
the detection of all SRLVs.
Thus, it would be interesting to conduct a
seroepidemiological
survey using such immunodominant synthetic peptides
to obtain
a comprehensive view on the relationships between the two
SRLV
clusters, i.e., CAEV and
MVV.
Nucleotide sequence accession numbers.
EMBL accession no.
AJ400718 to AJ400721 have been assigned to the SU nucleotide sequences
of CAEV isolates 680, 021, 032, and 786, respectively.
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ACKNOWLEDGMENTS |
We thank Thierry Vidard for excellent technical assistance and
Bernadette Trentin and Kathryn Mayo for critically reviewing the
English usage of the manuscript.
This work was supported in part by grants from the ANRS and the
Establissements Publics Régionaux d'Aquitaine et de
Poitou-Charentes.
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FOOTNOTES |
*
Corresponding author. Mailing address: AFSSA-Niort,
Laboratoire de Recherches Caprines, B.P. 3081, 60 rue de Pied de Fond, F-79012 Niort Cedex, France. Phone: (33) 5 49 79 61 28. Fax: (33) 5 49 79 42 19. E-mail: s.valas{at}niort.afssa.fr.
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