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Journal of Virology, July 2001, p. 6204-6208, Vol. 75, No. 13
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.13.6204-6208.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Role of the Promyelocytic Leukemia Protein PML in the Interferon
Sensitivity of Lymphocytic Choriomeningitis Virus
Mahmoud
Djavani,1
Juan
Rodas,1
Igor S.
Lukashevich,1
Douglas
Horejsh,1
Pier Paolo
Pandolfi,2
Katherine L. B.
Borden,3 and
Maria S.
Salvato1,*
Institute of Human Virology, University of
Maryland Biotechnology Center, Baltimore, Maryland
212011; Department of Human Genetics,
Memorial Sloan-Kettering Cancer Center, New York, New York
100212; and Department of Physiology and
Biophysics, Mount Sinai School of Medicine, New York, New York
10029-65743
Received 22 December 2000/Accepted 23 March 2001
 |
ABSTRACT |
Lymphocytic choriomeningitis virus (LCMV) induces type I interferon
(alpha and beta interferon [IFN-
and IFN-
]) upon infection and
yet is sensitive to the addition of type II interferon (gamma interferon [IFN-
]) to the culture media. This sensitivity is biologically important because it correlates inversely with the ability
of certain LCMV strains to persist in mice (D. Moskophidis, M. Battegay, M. A. Bruendler, E. Laine, I. Gresser, and R. M. Zinkernagel, J. Virol. 68:1951-1955, 1994). The cellular oncoprotein PML is induced by both IFN-/ and
IFN-, and PML binds the LCMV Z protein and becomes
redistributed within cells from nucleus to cytoplasm upon LCMV
infection. In the present study, increased PML expression results in
diminished LCMV replication, implicating PML in the IFN sensitivity of
LCMV. Virus production in PML 
/ murine embryonic fibroblasts (MEF)
exceeds virus production in PML +/+ MEF, and this difference is
exacerbated by IFN treatment that upregulates PML expression. IFN-
also diminishes LCMV production in PML / cells; therefore, viral
IFN sensitivity is not entirely due to PML. Both viral mRNA production
and viral protein production decrease as PML expression increases. Here
we propose that PML reduces LCMV transcription through its interaction
with the Z protein.
| |
TEXT |
Arenaviruses can replicate without
significantly impacting the host or causing cytopathic effects. The
arenavirus replication complex contains the viral genomic
single-stranded RNA segments, nucleocapsid protein (NP), an
RNA-dependent RNA polymerase (RdRp or L protein), and a small
zinc-binding protein (Z) (17). Cellular proteins are also
involved in viral replication (3, 4, 12). Here we describe
the inhibitory influence of the promyelocytic leukemia protein (PML)
that coprecipitates and colocalizes with cell-associated arenavirus
complexes (2). PML is an oncoprotein that is expressed
primarily in myeloid, epithelial, and endothelial cells, all infectable
by arenaviruses and important in the pathogenesis of arenaviral
hemorrhagic fevers. PML is induced by the alpha/beta interferons
(IFN-/) acting on the ISRE and GAS promoter
response elements (5, 13, 20). Interferons IFN- and
IFN- are produced by many cell types upon viral infection, and
IFN- is produced in T lymphocytes or natural killer cells in
response to antigens (16). IFNs are known for their
inhibitory effects on cellular proliferation, and PML, as an effector
of this function, is capable of suppressing cell proliferation
(11, 22, 24).
IFNs are also known for their antiviral effects. There are 50 to 100 IFN-inducible genes and several of them have antiviral activity, e.g.,
the p68 protein kinase, the 2',5'-oligoadenylate synthetase (OAS), and
certain Mx family proteins (19, 20, 23). The IFN-inducible
PML has also recently been shown to have antiviral activity. In the
absence of IFN, overexpression of PML diminishes infection by vesicular
stomatitis virus (VSV) and influenza A virus, without affecting
infection by encephalomyocarditis virus (EMCV), a virus known to be IFN
resistant (6).
Coimmunoprecipitation studies show specific interaction between PML and
Z proteins of LCMV and Lassa fever virus, a related arenavirus.
Genetically engineered mutations in PML were used to show that the Z
protein binds the N-terminal region of PML, and this domain of PML,
unlike the PML RING or the nuclear localization signal, is essential
for colocalization of Z and PML (2). The work presented
here demonstrates that PML expression diminishes LCMV expression,
possibly through its interaction with the LCMV Z protein.
PML and LCMV affect proliferation of MEF.
The effects of PML
expression on cell proliferation were examined in early-passage mouse
embryonic fibroblasts (MEFs) (22; this study). Fibroblasts
lacking PML (PML /) grew faster and achieved higher cell densities
than wild-type (PML +/+) cells and yet their cultures were
morphologically indistinguishable. IFN treatment, which increases PML
expression, reduces cell growth rates even more in both PML +/+ and
/ fibroblasts. Infection with LCMV shortens the life of both MEF
cultures approximately twofold (P < 0.05) (Fig.
1).
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FIG. 1.
PML expression and LCMV infection decrease the
proliferation of MEF. MEF from wild-type (PML +/+) or knockout (PML
/) mouse embryos were supplied by P. P. Pandolfi
(22) and were propagated in Dulbecco minimal essential
medium (DMEM; GIBCO, Grand Island, N.Y.) supplemented with 20% fetal
bovine serum (FBS). To measure cell proliferation rates, infected or
uninfected cells were seeded at 105 per 6-cm culture dish,
and viable cell counts were determined by trypan blue exclusion.
Infections employed LCMV-Armstrong 53b strain at an MOI of 1 PFU per
cell. The number of cells per dish represents the average of triplicate
measurements ± the standard deviation (SD).
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PML-expressing or IFN-treated MEF have reduced virus
replication.
Levels of LCMV replication were assessed in MEF with
or without PML. Cells were cultured and infected with LCMV for the
times indicated. This experiment was performed in two different ways to
minimize the effects of differing cell proliferation rates: virus
yields are described as the total PFU/milliliter in cultures that were
replated to achieve the same densities (Fig.
2A) or as the PFU/cell in cultures that
were terminated for cell counts at various intervals (Fig. 2B). The
highest virus yield in these cells was obtained at 48 h after
infection. At this time point, four- to fivefold increases in virus
yield were found in cells lacking PML (PML /) compared to PML +/+
cells.
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FIG. 2.
Replication of LCMV Armstrong in PML +/+ and PML /
MEF. Monolayer cultures of MEF (2 × 106 per T25
flask) were infected with LCMV-Armstrong at an MOI of 1 PFU per cell.
After a 1 h adsorbtion period, the inoculum was removed, fresh
DMEM with 20% FBS was added, and the cells were incubated at 37°C
for the different time points indicated. To determine virus yields,
culture media were frozen, and virus titers were determined by plaque
assay on Vero E6 cells as described earlier (8).
Titrations were performed on two separate occasions in duplicate wells
of a six-well plate, and the results are presented as the mean viral
yields ± the SD. (A) Virus yields (total PFU/milliliter) were
determined for the MEF of different PML genotypes. Cells were cultured
for 24-h intervals, after which media were collected for titration
and cells were trypsinized, counted, and replated to equalize the
numbers of PML +/+ and PML / cells/well for another 24-h culture
period. (B) Virus yields were normalized to cell number (PFU/cell) to
overcome the problem of different cell proliferation rates. In these
experiments, cell counts were determined after the medium was removed
for titration, and the cells were discarded after counting (i.e.,
separate cultures were used to determine each time point).
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Induction of PML expression by IFNs has been previously demonstrated by
Northern blot and immunofluorescence analysis (
22).
To
assess the capacity of murine IFN-
to inhibit LCMV replication,
both
PML +/+ and PML
/
MEF were treated for 48 h with 500, 1,000,
or 1500 U of IFN-
per ml, replated for equivalent densities,
and
then infected with LCMV at a multiplicity of infection (MOI)
of 1. To
minimize the contribution of cell proliferation to virus
replication,
virus titers were compared at the early time point
of 24 h. At
12 h postinfection, there would be no significant
differences in
viral replication, since that is only enough time
for one arenavirus
replicative cycle (
18). In the absence of
IFN, we found
only a twofold decrease in the virus yields in PML
+/+ cells compared
to the control PML
/
cells (Table
1)
that
could be attributable to different rates of cell proliferation.
IFN treatment similarly decreased the proliferation of both uninfected
and LCMV-infected MEF. In addition to the effects on cell
proliferation,
IFN affected virus production: significantly, a 16-fold
decrease
in virus yield was observed in IFN-treated PML +/+ cells
compared
to untreated PML +/+ cells (
P < 0.01). At
1,000 U of IFN, PML
+/+ cells produced fivefold less virus compared to
PML
/
cells
(
P < 0.05). Since IFN also inhibited
virus production in the PML
/
cells, additional IFN sensitivity
mechanisms (besides PML)
are involved in LCMV replication. Both PML +/+
and PML
/
MEF
express IFN-
/
but, unlike
IFN-
, these were not detectable by
Western blot (not shown) and were
probably at insufficient levels
to affect virus production.
Viral RNA levels are diminished in PML-expressing fibroblasts.
We examined whether the presence or absence of PML and the addition of
IFN in LCMV-infected MEF affects mRNA expression of viral genes. Total
cellular RNA was extracted from IFN-treated or untreated and
LCMV-infected MEF, reverse transcribed, PCR amplified in the presence
of random hexanucleotide primers (7), and subjected to
quantitative real-time PCR analysis.
To determine the levels of viral GP and NP cDNA relative to 18S
internal control, the following primer pairs were used: GP
(5'-TCATCGATGAGGTGATCAAC-3', 5'-CTTGGTGAACTCTCTAGACT-3'), NP
(5'-CAATGGACGCAAGCATTGAG-3',
5'-GTTCTTCTGCACTGAGCCTCC-3'),
and 18S rRNA primers (Ambion, Austin,
Tex.). Real-time PCR
employed a SYBR Green I PCR Core kit to produce
fluorescence-labeled
PCR products. Fluorescent NP and GP amplicons
were detected during the
course of the reaction using a Perkin-Elmer
GeneAmp 5700. The PCR cycle
at which the amplicon begins exponential
amplification is the threshold
cycle (C
T) which depends on the
starting concentration of
NP, GP, or 18S templates. The relative
levels of NP and GP messages are
derived by normalizing the NP
and GP C
T to the
C
T of 18S rRNA and comparing the results from
PCR
/
cells to results from PCR +/+ cells. Data calculations
are described in
Table
2, and Fig.
3 shows the final relative
quantitation
(RQ) values that indicate the excess of GP and NP
mRNA in PML
/
cells in comparison to these mRNAs in PML +/+
cells.
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FIG. 3.
Effect of IFN on viral mRNA transcription. MEF were IFN
treated, trypsinised 48 h later, counted, and then divided into
equivalent pools for LCMV infection. Recombinant mouse IFN- was from
R&D Systems, Minneapolis, Minn. Cellular RNA was extracted using TRIzol
(Life Technologies, Gaithersburg, Md.). The PCR cycle at which the
amplicon begins exponential amplification is the threshold cycle
(CT), which depends on the starting concentration of the
NP, GP, or 18S templates. The relative levels of the NP and GP messages
are derived by normalizing the NP and GP CT values to the
CT of 18S rRNA and then comparing results from PCR /
cells to results from PCR +/+ cells. In the exponential phase, a
CT difference ( CT) of 1 means that one
template is twice as abundant as the other. (Table 2 gives an example
of the actual data and calculations.) RQ values depend upon
CT (or the difference between the amplicon and the
standard in PML / cells and between the amplicon and the standard
in PML +/+ cells) such that RQ = 2  CT. Here the RQ value indicates the
relative excess of GP and NP mRNA in PML / cells in comparison to
the amounts of these mRNAs in PML +/+ cells.
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The analysis confirmed that the PML
/
cells had seven- to
elevenfold more NP mRNA than PML +/+ cells (
P < 0.05),
whereas
the PML
/
cells had only fourfold more GP mRNA than the
wild-type
cells (
P < 0.05) (Fig.
3, Table
2). A total
of 500 U of IFN per
ml showed no effect on LCMV RNA levels in
PML-expressing MEF compared
to PML
/
cells, but 1,000 U of IFN per
ml showed a mean 30%
decrease in both GP and NP mRNA in PML +/+ cells
compared to PML
/
cells. We conclude that IFN-
upregulates PML
and that this
upregulation affects LCMV RNA
production.
PML expression in MEF results in decreased expression of viral
proteins.
IFN treatment is known to upregulate PML expression at
both mRNA and protein levels (5, 13, 20, 22). To
investigate whether PML upregulation modulates the expression of viral
proteins, cells were grown in the presence or absence of IFN- and
infected with LCMV. Protein extracts from equal numbers of PML +/+ and PML / cells, treated or untreated with IFN, were compared on Western blots with respect to viral protein expression. The induction of PML resulted in the inhibition of LCMV antigen expression and was
confirmed by Western blot analysis using anti-LCMV antibodies (Fig.
4).
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FIG. 4.
Inhibition of LCMV gene expression in IFN-treated PML
+/+ and PML / MEF. (A) Cells were treated for 48 h with 500, 1,000, or 1,500 U of murine IFN- per ml, trypsinized, replated into
equivalent pools, and then infected with LCMV at an MOI of 1 PFU for
24 h. Western blot analysis of the MEF extracts was done as
described in the text. Blots were probed with our guinea pig anti-LCMV
antibodies and revealed by BCIP-NBT, an alkaline phosphatase substrate.
(B) The experiment in panel A was repeated; however, Western blots were
developed with a chemiluminescent probe and scanned with a
PhosphorImager (see the text). Scanning allowed us to attribute values
(the AQR) to the band intensities of the viral NP and to normalize
these values to an internal standard, murine actin. We considered the
amount of NP expressed by untreated PML / cells to be 100%, and we
presented the NP of all other cells as a percentage of this value.
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For Western blots, approximately 3 × 10
6 cells were
lysed in 0.5 ml of lysis buffer, and 30 µg of protein (8 × 10
4 cell equivalents) were loaded per lane as described
elsewhere
(
3,
10). The primary antibody was hyperimmune
guinea pig
polyclonal anti-LCMV serum (1:1,000), and the secondary
antibody
(1:10,000) was anti-guinea pig immunoglobulin conjugated to
alkaline
phosphatase or horseradish peroxidase (Sigma, St. Louis, Mo.).
Blots were developed using BCIP-NBT (Sigma) or enhanced
chemiluminescence
(Pierce, Rockford, Ill.). Chemiluminescence was
detected by scanning
with a PhosphorImager (Molecular Dynamics,
Sunnyvale, Calif.)
and using ImageQuant Software (Molecular Dynamics)
to compare
the scans of viral proteins to internal standards such as
murine
actin (Sigma). The area quantitation report (AQR) derived from
these scans was used to compare the relative amounts of one protein
and
another.
Only the most abundant viral proteins, NP and GP, were detected by our
polyclonal anti-LCMV sera. IFN treatment resulted in
a decrease of NP
and GP protein expression levels in both PML
+/+ and PML
/
MEF
(Fig.
4A). To determine the relative reduction
in NP expression, scans
of viral proteins (AQR) were normalized
to an internal standard, murine
actin, and the percent decrease
from NP expression in PML
/
cells
was expressed (Fig.
4B). Untreated
PML +/+ cells expressed 30% less NP
than untreated PML
/
cells.
Upon the addition of 1,000 U of IFN-
per ml, the highest inhibition
(>50% decrease) of LCMV protein
expression was observed in PML
+/+ cells. IFN treatment also caused a
slight drop in the level
of NP and GP proteins in PML
/
cells,
indicating that other
IFN-inducible genes are involved in antiviral
activity.
We conclude that LCMV replication is sensitive to the antiviral
activities of IFN, in part through the expression of the IFN-inducible
PML gene. IFN upregulates PML, and PML expression leads to reduced
production of LCMV. It has been shown that the overexpression
of PML
reduces production of VSV and influenza A virus but not
of an
IFN-resistant virus, encephalomyocarditis virus (
6).
The
PML inhibition of LCMV production was similar to the PML inhibition
of
VSV observed in infected CHO or MEF (
6,
13). Modest
(fivefold)
decreases in LCMV production were attributable to PML
expression.
Similarly modest (maximum of 16-fold) decreases were
attributable
to IFN (which includes PML effects). These effects are
biologically
significant because the IFN sensitivity of LCMV strains in
cell
culture correlates inversely with their ability to persist in
mice
(
15).
How PML inhibits LCMV replication is not known. In influenza virus and
VSV infections, it has been shown that PML expression
inhibits viral
antigen production and decreases viral titers,
but it was not
determined whether PML affects the transcription
of viral genes
(
6). We show here that PML expression causes
a decrease in
the steady-state levels of viral RNA, which we known
from previous
studies is approximately 1:100 (replicative RNA:mRNA).
The decrease in
mRNA levels could explain the observed decreases
in viral antigen
expression and in virus production, though it
is impossible to rule out
primary PML affects on virus translation
or assembly. Previously, we
showed that PML protein binds to the
LCMV Z protein (
2),
and we developed the working hypothesis
that PML sequesters Z from some
essential function in replication.
We also showed that PML and the Z
protein, separately, can have
translation-inhibitory effects
(
4). However, at this point,
there is no evidence to
distinguish whether the decreased levels
of viral RNA are due to
increased turnover or decreased de novo
synthesis.
The well-known antiproliferative effects of IFN-
treatment are
partially attributable to its induction of PML, which is proapoptotic
and antiproliferative (
1). PML dysfunction leads to
proliferation
of undifferentiated myeloid cells, which is a hallmark of
acute
myelocytic leukemia (
21). PML expression causes PML
+/+ MEF
to proliferate more slowly than PML
/
MEF
(
22). In a previous
publication we noted that LCMV
infection of a serum-starved culture
prolonged the life of the culture,
and we speculated that arenavirus
infection interferes with PML
function and prevents its normal
involvement in cell death
(
1). However, here we show, with
different fibroblastic
cells, that LCMV infection has an almost
twofold antiproliferative
effect (Fig.
1). Cell proliferation
rates are controlled by both
apoptotic pathways and cell cycle
progression, and LCMV infection has
separate effects on molecules
directing these processes (M.S.S. and
K.L.B.B., unpublished).
As yet, neither the pro- nor the
antiproliferative effects of
LCMV infection have been connected with
PML function or with the
function of any particular viral gene, i.e.,
these effects are
not attributable to expression of the Z gene alone,
since the
Z gene alone promotes cell death (
1).
Ultimately, to determine
the biological impact of PML on LCMV
replication, it will be necessary
to look at the ability of LCMV to
persist or cause disease in
PML-negative
animals.
In summary, our findings demonstrate that PML expression reduces cell
proliferation, that IFN exacerbates this reduction,
and that PML
expression downregulates the production of virus
particles, interfering
with both viral RNA and protein expression.
Thus, PML contributes
to the antiviral effect of
IFN.
| |
ACKNOWLEDGMENTS |
We thank Dave Pauza and Tracy Ruckwardt for helpful comments and discussions.
This work was supported by National Institutes of Health grant AI 32107 (to M.S.S.).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Institute of
Human Virology, University of Maryland Biotechnology Center, 725 W. Lombard St., Baltimore, MD 21201. Phone: (410) 706-1368. Fax: (410)
706-1992. E-mail: salvato{at}umbi.umd.edu.
| |
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Zhong, S.,
P. Hu,
T. Z. Ye,
R. Stan,
N. A. Ellis, and P. P. Pandolfi.
1999.
A role for PML and the nuclear body in genomic stability.
Oncogene
18:7941-7947[CrossRef][Medline].
|
Journal of Virology, July 2001, p. 6204-6208, Vol. 75, No. 13
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.13.6204-6208.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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