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J Virol, January 1998, p. 817-822, Vol. 72, No. 1
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Characterization of Provirus Clones of Simian Foamy
Virus Type 1
Ayalew
Mergia* and
Min
Wu
Department of Pathobiology, College of
Veterinary Medicine, University of Florida, Gainesville, Florida 32610
Received 25 July 1997/Accepted 28 September 1997
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ABSTRACT |
We have cloned proviral DNA of simian foamy virus type 1 (SFV-1)
from linear unintegrated DNA (pSFV-1). Transfection of pSFV-1 induces
cytopathology in several cell lines with supernatants from the
transfected cell culture containing infectious viral particles.
Electron microscopy of the transfected cells revealed foamy virus
particles. Deletion analysis of pSFV-1 indicated that the
transcriptional transactivator (tas) gene located between env and the long terminal repeat is critical for virus
replication, whereas the second open reading frame (ORF-2) in this
region is dispensable. Although the tas and ORF-2 regions
of foamy viruses have significantly diverged, the results presented
here suggested that the gene products have similar functions.
Recombinant pSFV-1 containing the cat gene was able to
transduce the heterologous gene, indicating the utility of SFV-1 as a
vector. An infectious clone of SFV-1 which is distantly related to the
human foamy virus will provide a means to understand the biology of
this unique group of viruses.
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TEXT |
Foamy viruses are a unique group of
retroviruses that belong to the Spumavirus genus. These
viruses are found in many mammalian species and are extremely
cytopathic in cell culture. Foamy viruses appear to be nonpathogenic in
naturally, as well as experimentally, infected animals. A human foamy
virus (HFV) and several simian foamy viruses (SFVs) have been
molecularly cloned, and their genomes have been completely sequenced
(4, 8, 12, 14, 16, 21). In addition to the structural genes,
the genome of foamy viruses contain regulatory genes. The human foamy
virus has three open reading frames (ORFs) located between the
env gene and the long terminal repeat (LTR). All of the
other foamy viruses molecularly characterized thus far have only two
ORFs in the corresponding region. The first ORF is a transcriptional
transactivator (tas, formerly known as taf) which
augments gene expression directed by the viral promoters (9, 11,
19, 22, 24, 30). For HFV, the tas gene has been shown
to be critical for virus replication (2, 13). The functions
of the other ORFs located between the env gene and the LTR
are not known and are dispensable for virus replication (2,
13).
Infectious clones of the HFV and the SFVs (SFVcpz, SFV-6, and SFV-7)
have been described (9, 13, 23, 29). The genomes of these
foamy viruses are highly related and have homology ranging from 86 to
93% (9). Comparisons of SFV-1 or SFV-3 to SFVcpz or HFV
show significant differences, especially in the tas and ORF-2 regions (9, 16). These ORFs of SFV-1 or SFV-3 are
related by less than 40% to SFVcpz or HFV. Tas of SFV-1 does not
activate gene expression directed by the HFV LTR promoter
(17). Similarly, Tas of HFV does not transactivate SFV-1 LTR
gene expression (24). Determining whether Tas or a gene
product containing the ORF-2 region of SFV-1 is critical for virus
replication has been hampered by the lack of an infectious clone.
Recently, it has been suggested that foamy viruses may have a
replication strategy different from those of other retroviruses, with
features of both hepadnaviruses and retroviruses, as well as features
distinct from both (3). Therefore, an infectious clone of
SFV-1 will help elucidate the unique features of foamy virus
replication. In addition, foamy viruses are currently being exploited
for use as retroviral vectors; thus, infectious clones of SFV-1
isolates will be advantageous. In this report, we describe the
construction of SFV-1 infectious clones, the effect of mutations in the
regulatory genes, and gene transfer of a reporter gene by an SFV-1
vector.
Construction and characterization of SFV-1 infectious provirus
DNA.
Total DNA from SFV-1-infected Cf2Th (canine fibroblast) cells
was isolated in accordance with a standard protocol (27). Foamy viruses produce large amounts of unintegrated linear DNA. The
plasmids containing the SFV-1 proviral DNAs were constructed by cloning
blunt-ended SFV-1 linear unintegrated DNA into a pUC118 plasmid. DNA
was subjected to agarose gel electrophoresis, and the region
corresponding to the size of unintegrated SFV-1 linear DNA was eluted.
The DNA was treated with T4 polymerase and Klenow fragment to create
blunt ends and was cloned into the HindII restriction enzyme site of plasmid pUC118. We have identified three types of
proviral clones (pSFV-1, pSFV-1/taorf2, and pSFV-1/enorf2; see Fig.
3A). The first type of clone had the full-length proviral genome
(pSFV-1). The second type of proviral clone we identified had a
deletion at positions 10,225 to 10,520 (pSFV-1/taorf2). This deleted
region corresponds to a region that gets spliced out to generate
bet transcripts (15, 20). The majority of the
proviral clones screened were the pSFV-1/taorf2 type. Proviral DNA
analogous to pSFV-1/taorf2 has also been described for HFV (26). It is proposed that this shorter provirus originated
from singly spliced RNA with joined exons of bet, and upon
reverse transcription of the singly spliced RNA, the shorter provirus accumulates in infected cells (26). However, it is not clear why this region is selectively spliced out at a higher rate to produce
a shorter proviral DNA. The third type of proviral clone had a deletion
from position 9,747 in the env gene to exactly the beginning
of the 3' LTR, at position 11,351 (pSFV-1/enorf2). This deletion
removes 76 amino acids at the carboxy terminus of env and
places the rest of the protein in frame with the carboxy-terminal 117 amino acids of ORF-2 located in the LTR.
To determine the infectious potential of pSFV-1, several cell lines
were transfected with 2 µg of the plasmid. Transfections were
performed by the liposome-mediated method using Lipofectamine Reagent
(Life Technologies, Inc., Gaithersburg, Md.). Transfected cells were
observed for up to 10 days for the appearance of a cytopathic effect
(CPE). Cells showed typical foamy virus cytopathology, which is
generally characterized as the formation of intracellular vacuoles in
multinucleated giant cells and, in some cases, balloon formation. The
extent of cytopathology and the rate at which it occurred varied among
the cell lines studied (Fig. 1A). In 293 (human fibroblast) cells, cytopathology was observed as early as 3 days
posttransfection. L-929 (murine fibroblast) cells and COS-7 (African
green monkey fibroblast) cells showed cytopathology beginning at days 6 and 8, respectively. Optimum cytopathology was observed at 10 days
posttransfection in all of the cell lines tested. pSFV-1-transfected
cells kept longer than 10 days in culture were completely destroyed as
a result of massive infection. Supernatants from these cultures were
monitored by reverse transcriptase (RT) assay for virus particle
release, and the RT values corresponded to the level of cytopathology
observed (Fig. 1B). The RT values from the later days posttransfection
were equivalent to those from cells infected with virus particles. To
establish whether the transfected cultures produced infectious virus
particles, media from transfected cells were cleared by filtration and
used to infect fresh cell lines permissive to SFV-1. Supernatants
harvested from all cells transfected with pSFV-1 transmitted virus
particles to uninfected cells as determined by the CPE on the infected
cells and RT analysis (data not shown).
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FIG. 1.
Infectivity of pSFV-1 in the 293, L-929, and COS-7 cell
lines. (A) Levels of CPE on infected cells at different time points
after pSFV-1 transfection. Levels of cytopathology were scored as
follows:  , no CPE; +, 10 to 20% CPE; ++, 30 to 50% CPE; +++, 60 to
70% CPE; ++++, 80 to 90% CPE. Lysis refers to greater than 99% loss
of cells in the infected cell culture. The numbers at the top indicate
days after DNA transfection or virus infection. (B) RT analysis of
supernatants from cell cultures transfected with pSFV-1 at different
time intervals. RT was assayed under conditions optimized for foamy
virus with Mn2+ cation (3). Samples were
harvested at the indicated time intervals in triplicate, and RT
activity was assayed. Less than 10% variation in replicate samples was
observed.
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EM examination of pSFV-1-transfected cells.
To demonstrate
that pSFV-1 generates mature viral particles, transfected L-929 cells
were examined by transmission electron microscopy. Cloned proviral
SFV-1-transfected cells were prepared for electron microscopy (EM) 10 days posttransfection, when significant cytopathology was noted. Cells
infected with wild-type SFV-1 were used as positive controls. These
cells were prepared for EM 4 days after infection, when cytopathology
was optimum. As shown in Fig. 2, viral
particles were detected in samples from virus-infected, as well as
pSFV-1-transfected, cells. The particles were spherical with the
prominent envelope spike structure typical of foamy virus, demonstrating that transfection of the recombinant clone pSFV-1 produced mature viral particles.
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FIG. 2.
Transmission EM analysis of virus particles from
pSFV-1-transfected (A) and SFV-1-infected (B) L-929 cells. Virus
particles are indicated with arrowheads (magnification, ×92,000). For
ultrathin sectioning, cells were fixed with 2.5% glutaraldehyde in
phosphate buffer at room temperature for 1 h, postfixed with 1%
osmium tetroxide for 1 h, dehydrated in a graded series of
ethanol, and embedded in Embed 812 (Polysciences, Warrington, Pa.).
Ultrathin sections were stained with uranyl acetate and lead citrate.
Stained sections were placed on grids and examined with a Hitachi H7000
transmission electron microscope (Hitachi Instruments, San Jose,
Calif.).
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Mutational analysis of pSFV-1.
For HFV, the tas
(bel-1) gene product was shown to be critical for virus
replication (2, 13). The Tas proteins of HFV and SFV-1 share
39% amino acid identity. Both proteins activate gene expression under
the control of viral promoters. To demonstrate that the tas
gene of SFV-1 is essential for virus replication, the region from
positions 10,008 to 10,202 was deleted from pSFV-1 (pSFV-1/dtas) and
tested for virus replication (Fig. 3).
Cells transfected with pSFV-1/dtas were monitored for 20 days for
cytopathology and for virus particles by RT assays. Transfected cells
lacked cytopathology, and neither culture supernatant nor extracts from three cycles of frozen-thawed cells indicated RT activity above the
background. This suggested that the tas gene of SFV-1,
similar to HFV tas, is critical for virus replication.
Cytopathology was noted in cells transfected with wild-type pSFV-1
beginning at day 6 and significantly increased at 10 days
posttransfection. Studies comparing SFV-1 and SFV-3 with HFV showed
that the U3 domains of the LTRs and the predicted amino acid sequences
of the tas genes have greatly diverged (16).
Consequently, Tas of either SFV-1 or HFV does not cross transactivate
gene expression directed by the heterologous LTR (18, 25).
Interestingly, however, the predicted proteins appear to have similar
structures, with short stretches that are highly conserved. Several of
these stretches have been determined to be critical for transactivation of gene expression directed by the viral LTR (7, 18, 31). These functional domains of Tas include a highly conserved
carboxy-terminal hydrophobic activation domain and basic rich regions
that include a nuclear localization signal. Therefore, although the
tas genes of foamy viruses have diverged, there are regions
that are conserved structurally and functionally, leading to a similar
regulation of virus replication.
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FIG. 3.
Mutational analysis of infectious pSFV-1. (A) Genome
organization of pSFV-1 and mutant derivatives. The hatched lines
represent the deleted regions. pSFV-1/taorf2 and pSFV-1/enorf2 are
proviral clones with natural deletions. (B) Effect of mutations on
virus replication. Plus and minus signs represent the presence and the
absence of a CPE, respectively. Samples for RT assays were harvested at
day 9 posttransfection.
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A deletion mutation was also introduced into the ORF-2 region, at
positions 10,872 to 11,208, to examine the effect of this
mutation on
SFV-1 replication (pSFV-1/dorf2) (Fig.
3). Transfected
cells showed
cytopathology beginning 6 to 8 days posttransfection.
The extent of the
CPE and RT values were similar to those of cells
transfected with
wild-type pSFV-1. Virus replication was not observed
in cells
transfected with either pSFV-1/taorf2 or pSFV-1/enorf2.
The
bel-2 and
bel-3 genes of HFV have been shown to
be dispensable
for in vitro virus replication (
2,
13). The
region encompassing
ORF-2 (
bel-2) also shows significant
variation between HFV and
SFV-1, which share only 38% homology.
Comparisons of the ORF-2
amino acid sequences from different foamy
viruses reveal short
stretches of highly conserved regions, implying
similar functions
for the proteins encoded by ORF-2 (
8,
16).
SFV-1 studies
presented in this report and HFV studies done by others
(
2,
9,
13) clearly indicated that foamy viruses can
replicate
in cell culture in the absence of the protein(s) encoded by
the
ORF-2 region. The postulated ORF-2 (
bel-2)-encoded
protein has
been identified as a 44-kDa protein by some investigators
(
5,
13), while others have failed to find an ORF-2 product
(
2,
7,
32). However, a
bet-encoded protein which
is a product
of a spliced message containing the first 88 amino acids
of Tas
fused to the last 390 amino acids of ORF-2 was found to be
highly
expressed in the cytoplasm of HFV-infected cells (
7,
20).
Proteins analogous to Bet have also been detected for SFV-1
(
6,
15). The function of
bet or ORF-2 remains to
be determined.
By using a sensitive assay, Yu and Linial
(
32) have determined
that mutations in the
bel-2
or
bet gene decreases cell-free virus
transmission about
10-fold, suggesting that either
bet or
bel-2 plays a role in efficient free virus transmission, similar to
vif of the lentiviruses.
Recombinant SFV-1 with a reporter cat gene.
Since
foamy viruses have been considered to be ideal vectors for gene
transfer, we tested the ability of cloned SFV-1 proviral DNA to
transduce a reporter cat gene. The cat gene was
placed downstream from the internal promoter (pSFV-1/cat), replacing the tas and ORF-2 regions at positions 10,225 to 11,208 (Fig. 4). A second recombinant was also
constructed by replacing the same region with the simian virus 40 (SV40) early gene promoter controlling cat expression
(pSFV-1/svcat). To determine the ability of these recombinants to
transduce the cat gene, an L-929 cell line expressing the
tas gene was established. The SV40 promoter was placed
upstream of the coding sequence of the tas gene, and this
plasmid construct was cotransfected with a plasmid expressing the
neomycin resistance gene (neo) into L-929 cells by
electroporation as described previously (1). Transfected
cells were grown in medium containing 1 mg of the neomycin derivative
G418 per ml. Neomycin-resistant colonies were propagated for four
rounds of single-cell cloning. To confirm the expression of
tas, we examined the level of gene expression directed by
either the viral LTR or the internal promoter by transfecting pSFV-1
LTR/CAT or pTM1/CAT, respectively, into the L-929-tas cell
line (Fig. 4). The construction of plasmids pSFV-1 LTR/CAT and pTM1/CAT
has been described previously (15, 17). For comparison, the
same plasmids were also used to transfect L-929 cells not expressing
the tas gene. Transfections were performed by the
DEAE-dextran method (1). For each chloramphenicol acetyltransferase (CAT) assay experiment, duplicate cell cultures were
transfected with 2 µg of the reporter plasmid and 3 µg of the
effector or carrier plasmid. Cell lysates were prepared 48 h after
transfection and assayed for CAT activity. Transient expression assays
of L-929 cells demonstrated very low basal promoter activity from these
constructs. In the established cell line containing the tas
gene, the expression of CAT by either the LTR (75-fold) or the internal
promoter (49-fold) was greatly increased. This observation indicated
that the L-929-tas cells were expressing the tas
gene.
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FIG. 4.
Assays of CAT reporter transient expression in cells
infected with recombinant virus particles containing the cat
gene. Recombinant pSFV-1 containing the cat gene
(pSFV-1/cat) or the cat gene under control of the SV40
promoter (pSFV-1/svcat) was constructed by replacing the indicated
region of the SFV-1 genome. Filtered supernatants from cell cultures
transfected with this plasmid were used to infect cells. pSFV-1
LTR/CAT41 and pTM1/CAT are positive controls transfected into cells to
monitor the level of CAT activity. p22A2 is a plasmid containing a
promoterless cat gene that was used as a negative control.
The values shown are from reactions measuring the conversion of
3H-acetyl coenzyme A to 3H-acetylated
chloramphenicol. Generally, less than 5% variation in replicate
samples was observed. The CAT values in L-929 cells represent basal
activity. Relative activity was calculated by dividing the CAT values
in L-929-tas cells by the basal levels in L-929 cells. To
calculate the relative activity for pSFV-1/svcat-infected cells, the
CAT value of pSFV-1/cat in L-929 cells was used as the basal level.
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Once we determined that the L-929-
tas cell line expressed
functional Tas, the pSFV-1 recombinant containing the
cat
gene (pSFV-1/cat
or pSFV-1/svcat) was transfected into the
L-929-
tas cell line.
Ten days after transfection,
supernatant was collected and filtered
through a 0.45-µm-pore-size
membrane filter. Supernatant containing
virus particles was used to
infect fresh L-929-
tas cells. Three
days following
infection, CAT assays were performed to determine
transduction of the
cat gene by SFV-1. As shown in Fig.
4B,
cat values were significantly higher than basal-level activity. Cells
infected with particles containing recombinant pSFV-1/cat or
pSFV-1/svcat
had CAT activity 19- or 25-fold higher than the background
level,
respectively. Cells infected with wild-type virus particles
harvested
from pSFV-1-transfected cells showed no CAT activity.
Furthermore,
no CAT activity was observed in L-929 cells infected with
pSFV-1/cat
transducing particles. The CAT value in L-929 cells infected
with
pSFV-1/svcat transducing particles was 12-fold higher than the
background level. These results suggested that pSFV-1 can be used
to
develop a vector system for gene transfer. Similarly, vectors
constructed based on HFV that encode heterologous genes were able
to
transduce a variety of cells (
25,
28). The HFV studies
done
thus far indicated that the foamy virus vector titers were
low.
However, Russell and Miller (
25) have shown that the
efficiency
of transduction of an HFV vector into stationary-phase
cultures
was higher than that of murine leukemia virus vectors.
Furthermore,
the efficiency of transduction by a foamy virus vector in
primate
hematopoietic cells compared favorably with those obtained with
murine leukemia virus vectors (
10).
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ACKNOWLEDGMENTS |
This research was supported by the National Institutes of Health
(AI39126 to A. Mergia).
We thank Soumya Chari for critical reading of the manuscript.
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FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pathobiology, College of Veterinary Medicine, University of Florida, P.O. Box 100145, Gainesville, FL 32610-0145. Phone: (352) 392-4700, ext. 3939. Fax: (352) 392-9704. E-mail:
aam{at}vetmed1.vetmed.ufl.edu.
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J Virol, January 1998, p. 817-822, Vol. 72, No. 1
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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