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Journal of Virology, December 2001, p. 12439-12445, Vol. 75, No. 24
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.24.12439-12445.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
A Unique Heparin-Binding Domain in the Envelope
Protein of the Neuropathogenic PVC-211 Murine Leukemia Virus May
Contribute to Its Brain Capillary Endothelial Cell Tropism
Atsushi
Jinno-Oue,
Miho
Oue, and
Sandra K.
Ruscetti*
Basic Research Laboratory, National Cancer
Institute
Frederick, Frederick, Maryland 21702-1201
Received 11 May 2001/Accepted 4 September 2001
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ABSTRACT |
Previous studies from our laboratory demonstrated that PVC-211
murine leukemia virus (MuLV), a neuropathogenic variant of Friend MuLV
(F-MuLV), had undergone genetic changes which allowed it to efficiently
infect rat brain capillary endothelial cells (BCEC) in vivo and in
vitro. Two amino acid changes from F-MuLV in the putative receptor
binding domain (RBD) of the envelope surface protein of PVC-211 MuLV
(Glu-116 to Gly and Glu-129 to Lys) were shown to be sufficient for
conferring BCEC tropism on PVC-211 MuLV. Recent examination of the
unique RBD of PVC-211 MuLV revealed that the substitution of Lys for
Glu at position 129 created a new heparin-binding domain that
overlapped a heparin-binding domain common to ecotropic MuLVs. In this
study we used heparin-Sepharose columns to demonstrate that PVC-211
MuLV, but not F-MuLV, can bind efficiently to heparin and that one or
both of the amino acids in the RBD of PVC-211 MuLV that are associated
with BCEC tropism are responsible. We further showed that heparin can
enhance or inhibit MuLV infection and that the mode of action is
dependent on heparin concentration, sulfation of heparin, and the
affinity of the virus for heparin. Our results suggest that the amino
acid changes that occurred in the envelope surface protein of PVC-211 MuLV may allow the virus to bind strongly to the surface of BCEC via
heparin-like molecules, increasing the probability that the virus will
bind to its cell surface receptor and efficiently infect these cells.
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TEXT |
PVC-211 murine leukemia virus
(MuLV), a neuropathogenic variant of the leukemia-inducing Friend MuLV
(F-MuLV) (13), causes a progressive neurodegenerative
disease in susceptible rodents (11, 19). The
primary target of PVC-211 MuLV infection is the brain capillary
endothelial cell (BCEC), with reactive astrocytes and degenerating
neurons within the central nervous system showing no evidence of virus
infection (11, 20, 22). Previous studies using chimeras
between F-MuLV and PVC-211 MuLV have demonstrated a direct correlation
between BCEC tropism and neuropathogenicity, with chimera PVF-e5
localizing the changes responsible for BCEC tropism to two amino acids
(Glu-116 to Gly and Glu-129 to Lys) which lie within the putative
receptor binding domain (RBD) of the envelope surface glycoprotein
(21) (Fig. 1).
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FIG. 1.
Genetic structures of MuLVs used in this study and
location of putative HBDs in their envelope proteins. (A) Comparison of
the genetic structures of F-MuLV, PVC-211 MuLV, and the chimera PVF-e5.
The envelope protein of PVC-211 MuLV has undergone two amino acid
changes from F-MuLV, Glu-116 to Gly and Glu-129 to Lys, that were shown
by the chimera PVF-e5 to be responsible for its unique BCEC tropism.
(B) Location of putative HBDs within the RBD of the MuLV surface
envelope protein (SU). Positions of variable regions and a proline-rich
domain similar to the immunoglobulin hinge region are shown
(7). A comparison of F-MuLV and PVC-211 MuLV sequences
within this region is shown below. Boxes indicate amino acid
differences that are associated with BCEC tropism. Brackets indicate
HBDs based on the consensus sequence XBBXBX, where X is any amino acid
and B is a basic amino acid (4). The substitution of Lys
at position 129 in PVC-211 MuLV creates an additional, overlapping HBD
in the RBD of this virus.
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It is not known how the genetic changes in the PVC-211 MuLV RBD result
in BCEC tropism. Both PVC-211 MuLV and F-MuLV utilize the cationic
amino acid transporter CAT-1 to enter cells (1), and it is
possible that the changes that occurred in the RBD of PVC-211 MuLV
allow this virus to bind more efficiently than F-MuLV to CAT-1
expressed on BCECs. Alternatively, the changes may allow PVC-211
virions to come in contact with the highly negative surfaces of BCECs
(9, 30), increasing the probability that they will interact with CAT-1. In support of the latter idea, we observed that
the changes in the PVC-211 MuLV RBD from Glu to Gly at position 116 and
from Glu to Lys at position 129 decreased the net negative charge of
the protein and created an additional heparin binding domain (HBD) in
the RBD of the virus; both of these features could allow PVC-211 MuLV
to bind efficiently to proteins containing heparin or heparan sulfate
on the surfaces of BCECs.
To date, two mammalian consensus HBDs have been described (XBBXBX and
XBBBXXBX, where X is any amino acid and B is a basic amino acid)
(4). As shown in Fig. 1B, PVC-211 MuLV and F-MuLV each
contain a linear HBD in the RBD. However, substitution of Lys at
position 129 in PVC-211 MuLV creates an additional, overlapping putative HBD in the RBD of this virus, raising the possibility that
PVC-211 MuLV may exhibit an increased affinity for heparin and that
this may allow the virus to efficiently infect BCECs through
interaction with heparin-like molecules on the surfaces of these cells.
Therefore, we compared the affinities of PVC-211 MuLV, F-MuLV, and
chimera PVF-e5 for heparin and tested whether exposure of virus or
cells to heparin could enhance or inhibit the infectivities of these
viruses for rat fibroblasts or BCECs.
Binding of virus to heparin.
The ability of virus to bind to
heparin was investigated by heparin-Sepharose chromatography of
concentrated virus particles. For these studies, virus was quantified
using a reverse transcriptase (RT) assay on cell supernatants, which
correlates strongly with expression of viral envelope protein as well
as with infectious virus titer as determined by a focal infectivity
assay on NIH 3T3 cells (data not shown). As shown in Fig.
2 and summarized in Table
1, a large amount of F-MuLV quickly passed through the heparin column (unbound virus), while only a small amount (15%) was
eluted with NaCl (bound virus). In contrast, a much smaller amount of
PVC-211 MuLV passed through the column, while a large amount was eluted
with NaCl (50%), indicating much stronger binding of PVC-211 MuLV than
of F-MuLV to heparin. To determine if the additional putative HBD in
the envelope protein of PVC-211 MuLV (Fig. 1) accounted for its
increased heparin binding, we utilized chimera PVF-e5 MuLV, which
contains this additional putative HBD on the background of F-MuLV
envelope sequences. As shown in Fig. 2 and Table 1, PVF-e5 MuLV bound
to heparin even more strongly than PVC-211 MuLV, with 71% of the virus
retained on the column. Western blotting of each fraction with an
anti-gp70 antiserum indicated that the envelope protein remained
tightly associated with virions during the course of separation on
heparin columns (data not shown). These results suggest that the change
from Glu-129 to Lys, and probably that from Glu-116 to Gly, in the RBD
of the envelope protein is critical in enhancing the affinity of viral particles for heparin.
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FIG. 2.
Heparin-Sepharose chromatography of virus. Concentrated
F-MuLV ( ), PVC-211 MuLV ( ), and PVF-e5 ( ) virions were
prepared by high-speed centrifugation and quantified using an RT assay
as previously described (16). Equivalent amounts of virus
(each corresponding to an RT activity of 2,500,000 cpm) were added to
heparin-Sepharose columns (HiTrap, Amersham Pharmacia Biotech.,
Piscataway, N.J.) equilibrated with 10 mM phosphate buffer (pH 7.4).
After collection of unbound viruses, bound viruses were eluted with
increasing NaCl concentrations ranging from 50 mM to 2.0 M. The RT
activity of each fraction was then determined.
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Effect of heparin on virus infectivity.
Anionic polymers such
as heparin and dextran sulfate have been reported to inhibit retrovirus
infection (2, 12, 15), while cationic polymers such as
DEAE-dextran or hexadimethrine bromide (Polybrene) enhance infection of
cells by most animal retroviruses (27, 29). Since PVC-211
and PVF-e5 MuLV can bind heparin significantly better than F-MuLV, we
carried out studies to determine if the infectivities of these viruses
for cells were modulated differently by heparin. Although MuLV
infections are usually carried out in the presence of Polybrene to
enhance infection, we carried out these experiments in its absence,
since Polybrene has been reported to inhibit the activity of heparin
(29). As shown in Fig. 3A,
in the absence of Polybrene, PVC-211 and PVF-e5 MuLV, but not F-MuLV,
can infect primary BCECs, while all three viruses were able to infect
Rat-1 fibroblasts (data not shown). Addition of Polybrene to the medium
(Fig. 3B) significantly enhanced infection of BCECs by F-MuLV as well
as by PVC-211 and PVF-e5 MuLV. These data were confirmed by Western
blotting with an antiserum to MuLV gp70 (data not shown).
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FIG. 3.
Susceptibility of primary rat BCECs to viral infection
in the presence and absence of Polybrene. Primary rat BCECs were
isolated from the brains of 21-day-old F344 rats and grown as
previously described (11). Cells were infected in the
absence of Polybrene (A) or in the presence of 5 µg of Polybrene/ml
(B) with equivalent amounts of F-MuLV (), PVC-211 MuLV (), or
PVF-e5 MuLV () based on RT activity (10,000 cpm). At various times
after infection, virion-associated RT activity in culture supernatants
was determined. Each data point is the mean of values for duplicate
samples.
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To determine the effects of heparin on virus infectivity in the absence
of Polybrene, virions were incubated with or without
various
concentrations of soluble heparin (from porcine intestinal
mucosa;
Sigma, St. Louis, Mo.) for 1 h at 37°C. The virus-heparin
mixture was incubated with cells for another hour, and then the
cells
were washed and cultured for 4 days (Rat-1 cells) or 7 days
(BCECs).
Replication of virus was evaluated by measurement of
virion-associated
RT activity in culture supernatants. Surprisingly,
concentration-dependent dual effects (enhancement and inhibition)
of
heparin on the infectivities of PVC-211 and PVF-e5 MuLV for
both Rat-1
fibroblasts and BCECs were found (Fig.
4A). Infection
was inhibited at high
heparin concentrations (>300 µg/ml) but
enhanced at low heparin
concentrations (<30 µg/ml). In contrast,
only inhibitory effects of
heparin on F-MuLV infection of Rat-1
fibroblasts were observed (Fig.
4A). F-MuLV is unable to infect
BCECs when Polybrene is excluded from
the medium (see Fig.
3A),
so the effect of heparin on F-MuLV infection
of these cells was
not tested. The effects of heparin do not appear to
be dependent
on multiple rounds of infection but rather reflect an
effect at
the level of viral entry. Using PCR to detect integrated
viral
DNA at 24 h postinfection, we were able to demonstrate that
the
level of integrated viral DNA increases and decreases in a
heparin-dependent
manner and directly correlates with the level of
virus detected
by the RT assay at 4 to 7 days postinfection (Fig.
4B).
This assay
is specific for viral entry, since integrated viral DNA
could
not be detected when cells were infected with MuLV that had been
preincubated with an anti-MuLV gp70 serum (data not shown).
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FIG. 4.
Effect of treating virus with heparin on virus
infectivity. Prior to infection, equivalent amounts (corresponding to
an RT activity of 10,000 cpm) of F-MuLV (), PVC-211 MuLV (), or
PVF-e5 MuLV () were incubated in the presence or absence of the
indicated concentrations of heparin for 1 h at 37°C. Then the
virus-heparin mixture was incubated with Rat-1 cells or primary rat
BCECs in the absence of Polybrene for 1 h at 37°C. To stop the
adsorption process, cells were washed and fresh culture medium was
added. (A) After 4 days (Rat-1) or 7 days (primary rat BCECs),
virion-associated RT activity in the culture supernatants was measured.
Results are expressed as RT activity relative to that in the control
(no heparin). Each data point is the mean ± standard error of the
mean of triplicate samples. (B) After 24 h, cellular DNA was
extracted and subjected to PCR analysis with primers specific for the
viral gag region (sense,
5'-CTGGGAGACGTCCCAGGGACTTCG-3'; antisense,
5'-GACCTGATCCGGATGTCCATGTGG-3'). The effect of treating
F-MuLV with heparin on BCEC infectivity was not determined because
these cells are already resistant to F-MuLV.
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It has been reported that heparin binds specifically to a number of
cell types, including endothelial cells (
8,
17,
23).
To
determine if heparin affects virus infection by binding to
the target
cells, Rat-1 fibroblasts or primary rat BCECs were
incubated with
increasing concentrations of heparin for 1 h at
37°C, washed to
remove unbound heparin, and incubated with virus
for 1 h at
37°C. After several days of culture, virus infection
was determined
by the RT assay. As shown in Fig.
5A,
treatment
of Rat-1 cells with heparin had little or no effect on
infection
by the BCEC-tropic viruses PVC-211 and PVF-e5 MuLV, whereas
F-MuLV
infection was inhibited in a dose-dependent manner. When primary
rat BCECs were incubated with heparin before virus inoculation,
heparin
had no significant effect on PVC-211 or PVF-e5 MuLV infection
(Fig.
5B). Heparin did not affect the infectivity of any of the
viruses for
Rat-1 cells or BCECs when it was added after virus
inoculation (data
not shown), indicating that its activity is
not due to alteration of
cell growth or inhibition of intracellular
viral RT activity. These
results suggest that heparin affects
the initial steps of
infection, such as the binding or fusion
of virus, and that the mode of
action of heparin on virus infectivity
is strongly dependent on its
affinity for the virus.
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FIG. 5.
Effect of treating cells with heparin on virus
infectivity. Rat-1 cells (A) or primary rat BCECs (B) were incubated
for 1 h in fresh medium containing heparin (1 to 1,000 µg/ml),
washed with medium, and then incubated with equivalent amounts of
F-MuLV (), PVC-211 MuLV (), or PVF-e5 virus () (RT activity,
10,000 cpm) for 1 h in the absence of Polybrene. Then cells were
washed, and fresh medium was added. After 4 days (Rat-1 cells) or 7 days (primary rat BCECs), virion-associated RT activity in the culture
supernatants was measured. Results are expressed as RT activity
relative to that in the control (no heparin). Each data point is the
mean ± standard error of the mean of triplicate samples.
Infection of Rat-1 cells by F-MuLV was significantly inhibited by
heparin (P < 0.05 by Student's t
test) at all concentrations tested. The effect of treating BCECs with
heparin on F-MuLV infectivity was not determined because these cells
are already resistant to F-MuLV.
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Heparin is known to be the most acidic polysaccharide in nature due to
its high extent of sulfation. To examine the importance
of the sulfate
in heparin for its effect on virus infection, desulfated
heparin was
tested for its ability to alter viral infectivity.
As shown in Fig.
6, de-
N-sulfated heparin,
which lacks
N-sulfate,
had little or no effect, compared to
unmodified heparin, on virus
infectivity (see Fig.
4). Thus, the
N-sulfate of heparin is essential
for its effect on virus
infection.
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FIG. 6.
Effect of de-N-sulfated heparin on virus
infection. Prior to infection, equivalent amounts (corresponding to an
RT activity of 10,000 cpm) of F-MuLV (), PVC-211 MuLV (), or
PVF-e5 MuLV () were incubated in the presence or absence of
indicated concentrations of de-N-sulfated heparin for
1 h at 37°C. Then the virus-de-N-sulfated
heparin mixture was incubated with Rat-1 cells (A) or primary rat BCECs
(B) in the absence of Polybrene for 1 h at 37°C. To stop the
adsorption process, cells were washed and fresh culture medium was
added. After 4 days (Rat-1 cells ) or 7 days (primary rat BCECs),
virion-associated RT activity in culture supernatants was measured.
Results are expressed as RT activity relative to that in the control
(no de-N-sulfated heparin). Each data point is the
mean ± standard error of the mean of triplicate samples. Heparin
(Fig. 4) and de-N-sulfated heparin were significantly
different (P < 0.01) in their effects on virus
infection. The effect of treating F-MuLV with
de-N-sulfated heparin on BCEC infectivity was not
determined because these cells are already resistant to F-MuLV.
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In conclusion, our results indicate that the level of binding of
PVC-211 MuLV to heparin is significantly higher than that
of F-MuLV and
that this can be attributed to one or both of the
amino acid changes in
the RBD of PVC-211 MuLV, particularly Glu-129
to Lys, which
creates a unique heparin binding site. Thus, the
ability of PVC-211
MuLV to bind heparin, combined with its decreased
negative charge, may
increase its interaction with the surfaces
of BCECs. Consistent with
this idea, we were able to use heparin
to modulate the infection
of BCECs or rat fibroblasts by MuLV;
the effect (enhancement or
inhibition) was dependent on heparin
concentration and sulfation and on
the affinity of the virus for
heparin.
Although the RBD of F-MuLV, as well as those of other ecotropic MuLVs,
contains a putative HBD, the virus binds poorly to
heparin. This may be
due to the presence of a negatively charged
glutamic acid residue in
the middle of this domain, which is unusual
among heparin binding sites
of published proteins (
3,
10)
and may inhibit efficient
binding to heparin. In contrast, the
unique HBD present in the PVC-211
MuLV envelope protein contains
residues commonly found in heparin
binding proteins, and it is
most likely responsible for the ability of
this virus to bind
to heparin efficiently. The second amino acid change
in the PVC-211
MuLV RBD that is associated with BCEC tropism
(Glu-116 to Gly)
may also contribute to the increased affinity of the
virus for
heparin, because this mutation (negatively charged amino acid
to nonpolar amino acid) would elevate the net positive charge
of the
RBD. Since our studies were carried out using intact virions,
the
unique HBD of PVC-211 MuLV must be exposed on the trimeric
envelope
glycoprotein structures known to exist on the surfaces
of MuLV
particles (
5). Interestingly, PVF-e5 MuLV, which contains
the RBD of PVC-211 MuLV on an F-MuLV background, has an even higher
affinity than PVC-211 MuLV for heparin. Perhaps the F-MuLV-derived
envelope gene sequences in PVF-e5 MuLV change the conformation
of the
envelope protein in the intact virion to better expose
the PVC-211
MuLV-derived HBD to
heparin.
Previous studies have shown that heparin can inhibit retroviral
infection, and our work extends those studies by showing that
the
effect of heparin on MuLV infection is strongly influenced
by the
affinity of the virus for heparin. Figure
7 is a schematic
representation of the
putative action of heparin on virus infection.
PVC-211 is normally able
to infect BCECs due to the presence in
the viral envelope protein of an
HBD which binds to heparin-like
molecules on the cell surface (Fig.
7A). In addition, the decreased
negative charge of the viral envelope
protein, due to the change
from Glu-116 to Gly, should also increase
the probability that
the virus will bind to the negatively charged cell
surface. Infection
of cells by PVC-211 MuLV is further enhanced by the
treatment
of the virus with low concentrations (1 to 30 µg/ml) of
heparin
(Fig.
7B). Since initial binding of MuLV particles to cells
does
not require specific envelope-receptor interactions
(
25), virus-bound
heparin might promote nonspecific
binding of virus to cells mediated
by a heparin binding molecule(s)
expressed on the cell surface.
Alternatively, a conformational change
in the envelope protein
induced by heparin binding (
24,
26) may increase the affinity
of the virus for CAT-1, its cell
surface receptor (not shown).
The high affinity of PVC-211 MuLV for
heparin is apparently required
for this enhancement, because exposure
of cells to heparin before
infection with virus did not lead to
enhancement of virus infection.
Infection of cells with PVC-211 MuLV is
inhibited by treatment
of the virus with high concentrations (>300
µg/ml) of heparin
(Fig.
7C). Increased amounts of virus-bound
heparin, cell-bound
heparin, and free heparin might inhibit attachment
of the virus
to the cell surface through electrostatic repulsions of
negatively
charged heparin. Infection of cells with F-MuLV is inhibited
by
treatment of cells with low or high concentrations of heparin
(Fig.
7D). In addition to lacking an effective HBD, the envelope
protein of
F-MuLV is much more negatively charged than that of
PVC-211 MuLV,
causing it to repel the negatively charged heparin
bound to the cell
surface. Thus, the net effect of heparin on
virus infection appears to
be dependent on the concentration of
heparin, the affinity of the virus
for heparin, and probably the
affinity and number of binding sites for
heparin on the target
cells.
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FIG. 7.
Schematic representation of a putative model for the
effects of heparin on virus infection. (A) PVC-211 MuLV infection of
BCECs; (B and C) PVC-211 MuLV infection of BCECs or Rat-1 cells; (D)
F-MuLV infection of Rat-1 cells. , soluble heparin;  ,
heparin-like molecules on the cell surface;  , heparin binding
proteins on the virus or the cell. Other negatively charged molecules
on the cell surface are not shown.
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The heparin-binding ability of PVC-211 MuLV may be related to its BCEC
tropism. We observed a direct correlation between the
heparin-binding
ability of MuLV and efficiency of replication
in primary BCECs.
Heparin-like molecules are expressed on the
surfaces of endothelial
cells, where they play a role in regulating
blood coagulation (
6,
14,
18). Due to the high negative
charge density of heparin,
BCECs would be expected to repel most
negatively charged MuLVs,
decreasing the probability that the
virus will be able to enter these
cells. However, creation of
an efficient heparin binding site within
the MuLV envelope protein
would allow it to bind to heparin-like
molecules on the surfaces
of BCECs. Thus, the amino acid changes that
occurred in the RBD
of the envelope surface protein of PVC-211 MuLV may
play an essential
role in determining the BCEC tropism of the virus by
allowing
the viral envelope protein to interact with heparin-like
molecules
on the surfaces of BCECs, increasing the probability that the
virus will bind the viral cell surface receptor, CAT-1, and enter
these
cells.
Further analysis will clarify the role of increased heparin binding
activity of BCEC-tropic viruses in the initial step of
infection.
Interestingly, PVC-441 MuLV, which is closely related
to PVC-211
MuLV but lacks the amino acid change at position 129
which creates the
unique HBD, can still infect BCECs in vitro,
albeit less efficiently
than PVC-211 MuLV (
28). PVC-441 MuLV,
like PVC-211 MuLV,
contains the Glu-116-to-Gly substitution, and
this change, in
conjunction with one or more of the 24 other amino
acids substituted in
its SU protein, may act to confer some level
of BCEC tropism on
the virus. The additional change of Glu-129
to Lys in the SU protein of
PVC-211 MuLV not only enhances the
efficiency of infection of BCECs by
PVC-211 MuLV but also results
in a virus that causes neurological
disease after a much shorter
latency period than that of PVC-441 MuLV
(30 days versus 60 to
73 days) (
28). Thus, the unique HBD
in the SU protein of PVC-211
MuLV may play an important role not only
in determining the efficiency
of infection of BCECs but also in the
development of neurological
disease in
vivo.
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ACKNOWLEDGMENTS |
We thank Paul Hoffman and Natalie Dugger, Department of Veteran
Affairs Medical Center, Baltimore, Md., for kindly preparing primary
rat BCECs.
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FOOTNOTES |
*
Corresponding author. Mailing address: Basic Research
Laboratory, Building 469, Room 205, National Cancer
InstituteFrederick, Frederick, MD 21702-1201. Phone: (301) 846-5740. Fax: (301) 846-6164. E-mail: ruscetti{at}ncifcrf.gov.
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Journal of Virology, December 2001, p. 12439-12445, Vol. 75, No. 24
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.24.12439-12445.2001
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