Journal of General Virology (1993), 74, 519-523. Printedin Great Britain
519
Molecular evidence that epizootic Venezuelan equine encephalitis (VEE)
I-AB viruses are not evolutionary derivatives of enzootic VEE subtype I-E
or II viruses
Judith M . Sneider, Richard M . Kinney, Kiyotaka R. Tsuchiya and Dennis W. Trent*
Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control
and Prevention, Fort Collins, Colorado 80522-2087, U.S.A.
Enzootic strains of Venezuelan equine encephalitis
(VEE) virus occur in the United States (Florida),
Mexico, Central America and South America. Epizootic
VEE first occurred in North and Central America in a
widespread outbreak between 1969 and 1972. To
investigate the likelihood that this epizootic VEE virus,
identified as VEE antigenic subtype I-AB, evolved from
enzootic viruses extant in the region, we cloned and
sequenced the 26S mRNA region of the genomes of the
Florida VEE subtype II virus, strain Everglades Fe3-7c,
and the Middle American subtype I-E virus, strain Mena
II. This region of the genome encodes the viral structural
proteins. The sequences of the 26S mRNA regions of the
Everglades and Mena virus genomes differed from that
of the reference epizootic VEE subtype I-AB virus,
Trinidad donkey strain, by 453 and 887 nucleotides and
by 66 and 131 amino acids, respectively. These data
confirm previous reports demonstrating significant antigenic and genetic distance between VEE I-AB virus and
viruses of subtypes I-E and II. It is unlikely that the
epizootic VEE I-AB virus responsible for the 1969
outbreak originated from mutation of enzootic VEE
viruses in North or Middle America.
Venezuelan equine encephalitis (VEE) virus is a
mosquito-borne alphavirus (Togaviridae family) that
has caused sporadic outbreaks of encephalitis in equine
species and humans in the Americas. The antigenically
defined complex of VEE viruses consists of six subtypes.
Subtypes I and III are further subdivided into five (AB, C,
D, E, F) and three (A, B, C) variants, respectively
(Young & Johnson, 1969; France et al., 1979; Kinney et
al., 1983 ; Calisher et al., 1982, 1985). Epizootic strains of
VEE virus, which have been isolated only during VEE
outbreaks, have consistently been subtype I-AB or I-C
viruses. Enzootic VEE viruses, which are maintained by
transmission between wild rodents and Culex (subgenus
Melanoconion) species mosquitoes, are avirulent for
equine animals (Young & Johnson, 1969; Johnson &
Martin, 1974, Sudia & Newhouse, 1975; Walton &
Johnson, 1972; Walton et al., 1973). An enzootic source
of equine-virulent, epizootic VEE virus has not been
identified.
Before 1969, VEE epizootics were limited to South
America, predominantly Venezuela and Colombia
(Groot, 1972). In the spring of 1969, an outbreak of VEE
I-AB virus occurred in Ecuador. Between 1969 and 1971
this epizootic spread to Central America, Mexico and the
United States (Texas). The mechanism of viral spread
from Ecuador to Guatemala and E1 Salvador in 1969,
from where it continued to advance, has remained an
enigma, since Panama was not involved in the outbreak
and epizootic VEE virus was not isolated in Panama
despite intensive surveillance. There is not irrefutable
evidence of epizootic VEE virus in Central America or
Mexico prior to 1969 (Franck & Johnson, 1971 ; Walton
& Johnson, 1972).
To investigate the likelihood that VEE viruses maintained in enzootic foci north of South America might
have been the source of the 1969 to 1972 epizootic I-AB
virus, we cloned and sequenced the 26S mRNA region of
the genomes of VEE subtype II virus, strain Everglades
Fe3-7c (EVE), and subtype I-E virus, strain Mena II
(MENA). The 26S mRNA of alphaviruses is identical to
the Y one-third portion of the genomic mRNA and
encodes the viral structural proteins, which are processed
from a polyprotein precursor (NH2-capsid-E3-E26K-E1-COOH) (Strauss & Strauss, 1986). The nucleocapsid protein and E1 and E2 envelope glycoproteins are
incorporated into VEE virions. VEE subtype II virus is
endemic in the Everglades region of Florida, U.S.A.
where Seminole Indians have shown a high prevalence of
The nucleotidesequencesreportedhave beensubmittedto GenBank
and assigned the accession numbers L01442 (TRD virus), L04598
(EVE virus) and L04599(MENA virus).
0001-1228 © 1993SGM
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520
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anti-VEE (subtype II) antibodies (Work, 1964; Chamberlain et al., 1964, 1969). EVE virus was isolated in 1963
from a pool of Culex (subgenus Melanoconion) species
mosquitoes collected in Everglades National Park, Fla
(Chamberlain et al., 1964). VEE subtype I-E virus is
endemic in Mexico and throughout Central America,
including western Panama (Grayson & Galindo, 1968;
de Mucha-Macias et al., 1966; Causey et al., 1961;
Scherer et al., 1972). MENA virus is a 1962 human
isolate from Almirante, Panama (Grayson & Galindo,
1968; Jahrling & Eddy, 1977).
Sequences of the structural genes of EVE and MENA
viruses were compared to those of the epizootic I-AB
virus, strain Trinidad donkey (TRD) (Kinney et al.,
1986, 1989), which is an equine isolate from the 1943
VEE epizootic in Trinidad (Randall & Mills, 1944). All
three viruses were plaque-purified in Vero cell monolayers (France et al., 1979). The passage histories of stock
seed viruses used, including plaque purifications, were
SM-4/Vero-6 for EVE virus, SM-3/Vero-7 for MENA
virus and GP-1/Vero-6 for TRD virus (where SM
denotes suckling mouse brain and GP is guinea-pig
brain). Nucleotide sequence analysis of virus cDNA was
performed as previously described (Kinney et al., 1986,
1989). Sequence compressions were resolved by substituting dITP for dGTP in sequencing reactions
(Sequenase sequencing kit, United States Biochemical
Corporation). Nucleotide differences in EVE virus, but
not in MENA virus, that resulted in amino acid
substitutions relative to the sequence of TRD virus were
confirmed on an independent cDNA clone.
Nucleotide sequences of the TRD virus genome and
the 26S mRNA region of the genomes of EVE and
MENA viruses were determined. Following alignment,
the sequence of the 26S mRNA region of TRD virus
differed by 453 (11"6%) and 887 (22.6%) nucleotides
from those of EVE and MENA viruses, respectively.
Although the sequences of EVE and MENA viruses
shared 166 identical nucleotide substitutions as compared to TRD virus, they differed from each other by 897
nucleotides (22"9%).
Alignment of the deduced amino acid sequences of the
structural polyprotein precursors encoded by the
genomes of VEE TRD, EVE and MENA viruses is
shown in Fig. 1. The polyprotein precursors of EVE and
MENA viruses differed by 66 (5"3%) and 131 (10.4%)
amino acids, respectively, from that of TRD virus; they
differed from each other by 145 (11.6%) residues and
shared 20 identical amino acid substitutions. Sequence
variation among the capsid proteins was greatest in the
highly hydrophilic domain (stippled bar in Fig. 1).
Sequences of the amino-terminal one-third portion of the
capsid proteins of alphaviruses are highly variable
(Dalgarno et al., 1983). A Cys (TRD)-to-Ser substitution
occurred at TRD capsid amino acid position 272 in the
capsid-E3 cleavage site of MENA virus. A Ser or Thr
residue also occurs at this position in the capsid proteins
of alphaviruses eastern equine encephalitis (EEE)
(Chang & Trent, 1987), western equine encephalitis
(WEE) (Hahn et al., 1988), Sindbis (SIN) (Rice &
Strauss, 1981), Semliki Forest (SF) (Garoff et al., 1980),
Ross River (RR) (Dalgarno et al., 1983), and O'nyongnyong (ONN) (Levinson et al., 1990) (data not shown).
The pE2 (E3-E2) cleavage site of MENA virus had a Lys
(TRD)-to-Gly substitution at position E3-57.
The E2 envelope glycoproteins of EVE and MENA
viruses differed from that of TRD virus by 32 (7.6 %) and
49 (11'6%) residues, respectively. Ten identical substitutions, including E2-57 Ser (TRD)-to-Pro and E2-75
Lys-to-Glu, occurred in both EVE and MENA viruses.
The E2-150 Ala (TRD)-to-Pro substitution in MENA
virus also occurs in EEE, SIN, SF, RR and ONN viruses
(data not shown). EVE and MENA viruses both lost a
potential Ash-linked glycosylation site (N-X-S or T,
where X denotes any amino acid) present at TRD virus
E2-291 or E2-212, respectively. Although the absence of
a carbohydrate moiety explains the lower apparent Mr of
the MENA virus E2 glycoprotein relative to TRD virus
E2 as observed by gel electrophoresis (France et al.,
1979; Wiebe & Scherer, 1980), the E2 glycoprotein of
EVE virus is nearly identical in size to that of TRD virus
(France et al., 1979; Kinney et al., 1983). Since all three
potential sites of glycosylation in TRD virus E2 appear
to contain carbohydrate (Mecham & Trent, 1982), we
are unable to explain the M r similarity between TRD and
EVE virus E2 proteins.
EVE and MENA virus E1 glycoproteins differed from
TRD virus E1 by 14 (3"2%) and 34 (7'7 %) amino acids,
respectively. Five identical amino acid substitutions,
including a Ser (TRD)-to-Asn change at El-9, occurred
in EVE and MENA virus E1 proteins. The El-9 Ser
(TRD)-to-Asn substitution in EVE and MENA viruses
and the El-14 Ser (TRD)-to-Pro substitution in MENA
virus also occur in the E1 proteins of EEE, WEE, SIN,
SF, RR and ONN viruses (data not shown).
Variations in the nucleotide and amino acid sequences
of the structural proteins of VEE subtype I-AB, I-E and
II viruses confirm relationships previously demonstrated
by antigen analysis (Young & Johnson, 1969; France et
al., 1979), tryptic peptide mapping (Kinney & Trent,
1982) and oligonucleotide fingerprinting of genomic
RNA (Trent et al., 1979). Mutations in monoclonal
antibody neutralization escape variants of SIN (Strauss
et at., 1987, 1990; Davis et al., 1987) and VEE (Johnson
et al., 1990) viruses map between E2 amino acid positions
182 and 209, and attenuating mutations in this domain
of VEE virus have been identified (Johnson et al., 1990;
Davis et al., 1991). Amino acid substitutions that occur
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521
C
TRD
EVE
NENA
TRD
EVE
MENA
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.......................................................
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AQNGNKKKTMKKPGKRQRNVI4KLESDKT FP I NLEGK l NGYACWGGKL FRPI4HVEGKI DNDVLAALKTKKASKYDLEYADVPQNHRADT
L.
PQ.
FKYT HEKPOGY
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C -199
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C -198
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*
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TRD
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NENA
YSWHHGAVQYENGRFTVPKGVGAKGDSGRP l LDNQGRWA l VLGGVNEGSRTAL SWI~MEKGVTVKYTPENCEQI SLVTTNCLLANVT FPCAOPP I CY
..................
R.... R...........................................................................
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.........................................................
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E 3 - 23
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DRKPAETLANLSVNVDNPGYOE L LEAAVKCPGRKR
EL FKEYKLTRPYNARC I RCAVGSCHSPIA ] EAVKSDGHDGYVRLQTSSQYGLDSSGNLKG
............
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E 2 - 63
E Z - 63
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RTNRYDNHGT l KE I PLHQVSLHTSRPCH I VDGHGY FLLARCPAGOS i TNEFKKDSVT HSCSVPYEVKFNPVGRELYTHPPEHGVErJACQVYAHDAQNRGA
..... N.Y...E .......................................................................
A ................
...........
E .................
I .......................
E .............................
A..P.H ...........
E2-163
E2-163
E2-16]
TRD
EVE
NENA
YVE•tiLPGSEVD•sL•SL•GSS•T••PPVGTSALVE•EC•GTK•S•T•NKTKQFS•CTKKE•CRAYRLQ•DK1•NYNSDKLPKAAGATLKGKLHVPFLLAD
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NENA
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...........................
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....................
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............................................................
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...............
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EVE
NENA
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...............................................
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..............
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....
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Fig. l. Alignment of the deduced amino acid sequences of the translated regions of the 26S mRNAs of VEE TED, EVE and MENA
viruses. Deletions (-) have been introduced in the EVE and MENA capsid (C) proteins to optimize alignment. Solid dots indicate amino
acid sequence identity with TRD virus. Asterisks (*) indicate the potential Ash-linked glycosylation sites (N-X-S or T, where X denotes
any amino acid) of TRD virus. The stippled bar indicates the highly hydrophilic region of the capsid protein and the solid bars indicate
probable transmembrane domains as predicted by the algorithm of Kyte & Doolittle (1982). A correction to the previously published
TRD sequence (Kinney et al., 1989), an insertion of a Gly residue (!) near the carboxyl end of the 6K polypeptide, is shown.
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522
Short communication
within or near this domain of the E2 proteins of both
EVE and MENA viruses probably account for much of
their differential antigenicity in polyvalent (Young &
Johnson, 1969; France et al., 1979) and monoclonal
(Roehrig et al., 1982; Roehrig & Mathews, 1985)
antibody analyses. Other E1 and E2 amino acid
substitutions, including those which result in the loss of
a potential site of glycosylation, as well as altered
cleavage sites in the viral structural polyprotein precursor, may also affect the biological phenotypes of EVE
and MENA viruses.
The 26S mRNAs of EVE and MENA viruses differed
considerably from that of TRD virus in nucleotide
sequence. The MENA strain of VEE subtype I-E virus
that occurs in Mexico and Central America, the region
predominantly affected by the 1969 to 1972 VEE
epizootic, differed from TRD virus at nearly one-fourth
of the 26S mRNA nucleotide positions. It is unlikely that
the VEE I-AB virus of the 1969 to 1972 epizootic
originated from enzootic subtype I-E or II virus. The
literature indicates that evolution of new world alphaviruses is quite slow (Weaver et al., 1992a). Since the
epizootic virus responsible for this widespread outbreak
appeared to have originated in Ecuador in 1969, it is
possible that the virus arose by mutation of the more
closely related enzootic VEE subtype I-D virus that
occurs in South America. Rico-Hesse et al. (1988),
Weaver et al. (1992b) and Kinney et al. (1992a) have
reported genetic evidence indicating that epizootic VEE
virus most likely evolved from enzootic VEE subtype ID virus. We have identified 225 nucleotide and 23 amino
acid substitutions in the 26S mRNA region of the
Panamanian 3880 strain of VEE subtype I-D virus,
relative to that of TRD virus (Kinney et al., 1992a).
Young (1972), who noted the distinctness of epizootic
I-AB and enzootic I-E viruses, speculated that the
epizootic virus originated from formalin-inactivated
I-AB vaccine. Epizootic VEE subtype I-AB viruses
TRD, PTF-39 (a 1969 isolate from Guatemala) and
several 1971 isolates from Texas were nearly identical
genetically as shown by oligonucleotide fingerprinting of
genomic RNAs (Trent et al., 1979; Monath et al., 1992).
The entire genome of an epizootic VEE I-AB isolate,
strain 71-180, from the 1971 epizootic in Texas has been
sequenced. The genome of this isolate differed from that
of TRD virus, isolated in 1943, by only 34 nucleotides, 19
of which occurred in the 26S m R N A region of the
genome (Kinney et al., 1992b). Since formaldehydeinactivated preparations of virulent VEE I-AB virus,
including the TRD strain, were widely used as VEE
vaccine in the field (Kubes & Rios, 1939; Beck &
Wyckoff, 1938; Randall et al., 1949), we consider the
most likely aetiology of the 1969 to 1972 panzootic,
and perhaps other epizootics of VEE I-AB virus, to have
been residual live virus in incompletely inactivated
formalin preparations of equine virulent, epizootic VEE
I-AB virus.
This research was supported by the U.S. Army Medical Research
and Development Command, Fort Detrick, Frederick, Maryland
21701, U.S.A. Contract Number 87PP7876.
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(Received 13 July 1992; Accepted 30 October 1992)
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