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Journal of Virology, August 1999, p. 6559-6565, Vol. 73, No. 8
Department of Genetics and Microbiology,
University of Geneva School of Medicine, CMU, CH1211 Geneva,
Switzerland
Received 16 March 1999/Accepted 5 May 1999
We have studied the relationship between the Sendai virus (SeV) C
proteins (a nested set of four proteins initiated at different start
codons) and the interferon (IFN)-mediated antiviral response in
IFN-competent cells in culture. SeV strains containing wild-type or
various mutant C proteins were examined for their ability (i) to induce
an antiviral state (i.e., to prevent the growth of vesicular stomatitis
virus [VSV] following a period of SeV infection), (ii) to induce the
elevation of Stat1 protein levels, and (iii) to prevent IFN added
concomitant with the SeV infection from inducing an antiviral state. We
find that expression of the wild-type C gene and, specifically, the
AUG114-initiated C protein prevents the establishment of an
antiviral state: i.e., cells infected with wild-type SeV exhibited
little or no increase in Stat1 levels and were permissive for VSV
replication, even in the presence of exogenous IFN. In contrast, in
cells infected with SeV lacking the AUG114-initiated C
protein or containing a single amino acid substitution in the C
protein, the level of Stat1 increased and VSV replication was
inhibited. The prevention of the cellular IFN-mediated antiviral response appears to be a key determinant of SeV pathogenicity.
Interferons (IFNs) are a family of
cytokines originally identified by their ability to confer cellular
resistance to viral infection (14) and which are also
involved in cell growth regulation and immune activation (30,
33). Infection of cells with a wide variety of viruses directly
induces the transcription and synthesis of some IFNs (e.g., IFN- Sendai virus (SeV), a model paramyxovirus routinely used to induce type
I IFNs in cell culture, is a naturally occurring respiratory pathogen
of laboratory mice (15). SeV strains exist which differ markedly in their pathogenicity for mice, but the determinants of their
virulence are largely unknown. Our reference SeV strain, Z, was
originally isolated in the early 1950s in Japan and adapted to grow in
embryonated hen's eggs. This adaptation and continuous passage in eggs
undoubtedly reduce its virulence for mice, because the 50% lethal dose
(LD50) of SeVZ is ca. 6 × 103, whereas that of the more recently isolated Ohita field
strain (from a lethal animal house epidemic and which was passaged only in mice [SeVM]) is ca. 4 × 101
(16). SeVM, however, grows poorly in cell
culture, and its adaptation for growth in LLC-MK2 (monkey kidney) cells
led to virus clones that exhibited various degrees of reduced
pathogenicity for mice. One of these clones, MVC11 (SeVMVC)
appeared to be totally avirulent (LD50 of >8 × 105 [i.e., none of the mice died at the highest possible
dose]).
Remarkably, SeVMVC contained only two amino acid
substitutions relative to the parental SeVM, namely, F170S
in the C proteins, and E2050A in the L protein (Fig.
1) (16). These two mutations
presumably account for the relative inability of SeVMVC to
replicate in the mouse respiratory tract and cause serious disease. In
a previous study, we partially examined which of the two substitutions
was responsible for the phenotypes described above by exchanging the C
gene of SeVZ with that of itself, SeVM, or
SeVMVC in turn (generating the recombinants
rSeVZ-CZ, rSeVZ-CM, and
rSeVZ-CMVC, respectively [Fig. 1])
(12). Wild-type rSeVZ-CZ (recovered
from DNA) has the same virulence for mice as the natural Z virus
(LD50 of ca. 6 × 103), and the
replacement of the resident CZ gene with that of strain M
did not affect this virulence. Replacement of the resident
CZ gene with CMVC in two independently isolated
viruses, however, increased the LD50 of
rSeVZ-CMVC by >2 logs, such that the viruses
were now as avirulent as SeVMVC. Because the only known
difference between rSeVZ-CM and
rSeVZ-CMVC is the CF170S mutation,
the normal function of the C proteins appears to be required for
virulence in mice. The wild-type SeV C proteins are also known to act
as promoter-specific inhibitors of viral RNA synthesis (1, 28,
32). The CF170S mutation is similarly associated with
the loss of this function and is at least partially responsible for the
enhanced replication of these viruses in MK2 cells.
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Sendai Virus C Proteins Counteract the
Interferon-Mediated Induction of an Antiviral State
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
4
and IFN-
) (24, 34). These IFNs are secreted and interact
with constitutively expressed cell surface receptors in an autocrine or
paracrine manner, transducing signals via the JAK-STAT pathway to
activate >50 IFN-stimulated genes, which include the type I IFNs
(6). Some of these IFN-stimulated genes are responsible for
the versatile biological effect of IFNs, including their antiviral
activity. In addition to establishing an antiviral state in uninfected
cells, the IFN system helps eliminate virally infected cells
(38). The IFN system is thus thought to be essential for the
survival of higher vertebrates, because it provides an early line of
defense, days before the onset of the specific immune response
(33).
View larger version (17K):
[in a new window]
FIG. 1.
Genotypes and phenotypes of the SeV strains examined.
The genotypes of the various SeV strains examined in this study are
represented as rectangles on the left, in which the linear arrays of
genes (not drawn to scale) are shown as boxes. The relative positions
of the C and V ORFs, which overlap the P ORF, are also indicated. M
strain sequences are white, Z strain sequences are gray, and H strain
sequences are hatched. These rSeVZ strains all carry a
tagged N gene, from which this protein migrates differently on SDS-PAGE
than that of strain Z, to distinguish these viruses from natural
SeVZ. The amino acids at positions 170 of the C gene and
2050 of the L gene are shown below the genomes. The phenotypes of these
virus infections of mice (LD50) are taken from references
12 and 16. Those of BF cells,
including the ability of VSV to replicate (repl.) following a period of
SeV infection (a) and to prevent IFN from establishing an antiviral
state (b) and the resulting intracellular levels of the Stat1 proteins
(c) were determined in this study.
Although rSeVZ-CMVC was avirulent, it appeared to grow normally in the mouse respiratory tract during the first day of the infection. However, whereas virus titers in rSeVZ-CM or rSeVZ-CZ-infected mice lungs increased daily for ca. 5 days, virus titers in rSeVZ-CMVC-infected mice increased only during the first day, and rSeVZ-CMVC was then quickly cleared from the lungs (12). A similar early restriction of the mouse infection was found for rSeV strains which specifically cannot express their AUG114-initiated C protein (22) or which cannot edit their P gene mRNA and therefore do not express their V proteins (7, 8, 19). The rapidity of the host antiviral response in immunologically naive mice in limiting the ensuing mutant SeV infections suggested that some aspect of host innate immunity might be involved, presumably due to the loss of V and C protein function. In this view, one function of the SeV C and V proteins would be to modulate the innate immune response, in order to sustain multiple cycles of virus replication in the mouse respiratory tract (19). In this paper, we report that the SeV C proteins play a role in counteracting the IFN-mediated cellular antiviral response.
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MATERIALS AND METHODS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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SeV stocks and infection. The generation of rSeV strains expressing alternate C (and P) proteins has been described previously (11-13, 22). All SeV stocks were grown in the allantoic cavity of 10-day-old embryonated chicken eggs. Viruses from allantoic fluid stocks were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Coomassie blue staining after pelleting, and titers were determined by plaquing in LLC-MK2 cells.
The vesicular stomatitis virus (VSV) stock (Mudd-Summers, Indiana) was grown in BHK cells. Virus released into the culture medium was clarified by centrifugation at 10,000 × g to remove cell debris, and the titer was determined by plaquing in LLC-MK2 cells. Experiments were performed by infecting (7 × 106) mouse BF cells (36) with various SeV stocks at a multiplicity of infection (MOI) of 10 to 20 in a total volume of 3 ml of minimal essential medium plus 8% fetal calf serum in the presence or absence of 100 U of recombinant mouse IFN- per ml (Calbiochem).
At different times postinfection, cells were superinfected with VSV at
an MOI of 50. Five hours later, cells were harvested and then lysed in TNE (10 mM Tris-Cl, pH 7.4, 100 mM NaCl, 1 mM EDTA) plus 0.5% Nonidet
P-40. Proteins were analyzed by immunoblotting, and RNA was extracted
with Triazol (Gibco) and analyzed by primer extension.
Immunoblotting. Proteins were separated by SDS-PAGE and transferred to Immobilon-P membranes by semidry transfer. The primary antibody antibodies used included a rabbit polyclonal antiserum to VSV P protein (provided by J. Perrault and D. Summers), a rabbit polyclonal antiserum to SeV P protein isolated from an SDS gel (anti-PSDS, provided by L. Roux), a mouse monoclonal antibody to SeV N (N 877) (27), a mouse monoclonal antibody to Stat1 (C terminus) (Transduction Laboratories [S21120]), rabbit polyclonal antiserum to actin (provided by G. Gabbiani, Geneva, Switzerland), and rabbit polyclonal antiserum to SeV C protein (provided by Y. Nagai, Tokyo, Japan).
The secondary antibodies used were alkaline phosphatase-conjugated goat antibodies specific for either rabbit or mouse immunoglobulin G (Bio-Rad). The immobilized proteins were detected by light-enhanced chemiluminescence (Bio-Rad) and quantified by using the Bio-Rad Fluor-S multimager.Primer extension. Total intracellular RNA was isolated with Triazol, and the genomes present were analyzed by primer extension with Moloney murine leukemia virus reverse transcriptase and 200,000 cpm of 32P-labeled 5'-GAAGCTCCGCGGTACC-3' (nucleotides 15270 to 15285), which had been purified on a sequencing gel.
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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As mentioned above, SeVMVC was selected for its
ability to replicate more efficiently than SeVM in LLC-MK2
cells, and it was found to accumulate ca. 20-fold more viral protein
and mRNA than SeVM-infected cells (reference
16 and data not shown). In BF cells, a cell line
that is fully IFN competent (i.e., that secretes IFN in response to a
viral infection and responds to IFN by establishing an antiviral state
[36]); however, SeVM actually grows
slightly better (three- to fivefold) than SeVMVC, as
estimated by the intracellular levels of viral proteins or genomes
(Fig. 2A to D, lanes 1, 3, and 4). To
examine whether IFN might be involved in this reversed
SeVM-SeVMVC replication efficiency, parallel BF
cultures were pretreated with 100 U of IFN- for 24 h prior to
SeV infection, and the accumulation of viral proteins and genomes was
determined. SeVMVC was found to be highly IFN sensitive,
because IFN pretreatment reduced the accumulation of viral products
>20-fold, (Fig. 2B and D, lanes 2, 5, and 6). SeVM, in
contrast, was clearly less sensitive, because IFN pretreatment reduced
the accumulation of viral products less than fivefold (Fig. 2A and C,
lanes 2, 5, and 6).
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If endogenously generated IFN is involved in the reversed
SeVM-SeVMVC replication efficiency in BF cells,
infection with SeVMVC should induce a general antiviral
state more strongly during this infection than infection with
SeVM. The rhabdovirus VSV is highly IFN sensitive, and its
inability to grow in cell culture is considered a reliable indicator of this state. Some BF cultures were therefore pretreated with IFN- for
24 h prior to SeVM or SeVMVC infection and
then superinfected with VSV at 48 h postinfection (hpi). We found
that 48 h of SeVMVC infection was sufficient to
prevent VSV proteins from accumulating during the VSV superinfection,
even when these cultures had not been pretreated with IFN (Fig. 2F,
lanes 3 to 6). In contrast, VSV proteins accumulated normally during
the superinfection of cells infected with SeVM for 48 h (Fig. 2E, lanes 3 and 4). Thus, infection of BF cells with
SeVMVC induces an anti-VSV state (after 24 to 48 h
[data not shown]), whereas infection with SeVM does not
induce this state, even at 72 hpi (data not shown). In all of the
experiments reported here, the appearance of normal levels of VSV P
protein on superinfection correlated with strong cytopathic effects and
cell death, whereas the absence of VSV P protein correlated with the
absence of cytopathic effects and cell survival.
SeVM infection, but not that of SeVMVC,
interferes with the IFN-mediated induction of an antiviral state.
The absence of an anti-VSV state following SeVM infection
could be because SeVM avoids triggering the IFN system.
Alternatively, SeVM infection may interfere with the
establishment of an antiviral state, even though it does not suppress
the anti-VSV state induced by 24 h of IFN pretreatment (Fig. 2E,
lanes 5 and 6). BF cultures were therefore treated with IFN at the same
time as they were infected, so that the IFN-mediated induction of the
antiviral state would take place concomitantly with the SeV infection
and not have a 24-h head start as in Fig. 2. These cultures were then superinfected with VSV at 50 h post-SeV infection, and the
accumulation of VSV (and SeV) proteins was determined by immunoblotting
at 55 hpi. The intracellular levels of the 91-kDa Stat1 and 84-kDa Stat1 proteins in these extracts were also determined by
immunoblotting. Stat1 is a key component of the signaling cascade which
ensues with activation of the IFN receptor (6, 9, 26), and
its elevated expression leads to programmed cell death (PCD), another cellular response to virus infection (3, 20, 29).
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The role of the C protein. SeVM and SeVMVC differ by two amino acid substitutions, CF170S and LE2050A (Fig. 1). To examine the role of the C gene mutation in suppressing the ability of SeVM to interfere with the establishment of an IFN-mediated antiviral state, we examined the infection of BF cells with rSeVZ-CM and rSeVZ-CMVC. These are chimeric viruses in which the resident C gene of SeVZ (and the overlapping portion of the P gene) was replaced with those of SeVM and SeVMVC. (The P genes of the M and Z strains are 85% identical.) rSeVZ-CM and rSeVZ-CMVC thus differ only by the CF170S mutation. rSeVZ-CZ, in which the C gene was exchanged with itself as a cloning control (12), served as the wild-type rSeVZ. As shown in Fig. 3, rSeVZ (lanes 5 and 6) and rSeVZ-CM (lanes 11 and 12) behaved similarly to wild-type SeVM (lanes 7 and 8). Fifty hours of these infections did not prevent the VSV P protein from accumulating normally on VSV superinfection, nor did it increase Stat1 levels over background levels. These infections also prevented IFN from inducing an anti-VSV state. In contrast, 50 h of infection with rSeVZ-CMVC (lanes 13 and 14) strongly induced an anti-VSV state even in the absence of IFN treatment, but led to only a very modest increase in Stat1 levels over background levels (lane 13). This slight increase, however, is superior to that induced with IFN alone (lane 2), and IFN treatment plus rSeVZ-CMVC infection appeared to act synergistically on Stat1 levels (lane 14). Thus, viruses that contain a wild-type C gene (SeVM, rSeVZ-CM, or rSeVZ-CZ [all CF170]) appear to interfere efficiently with the establishment of an IFN-mediated antiviral state, in contrast to those with a mutant C gene (SeVMVC and rSeVZ-CMVC [both CS170]). The C proteins thus appear to be important in determining whether SeV infection will induce an antiviral state.
The AUG114-initiated C protein is specifically required
to counteract IFN.
The SeV C proteins are expressed as a nested
set of four proteins (C', C, Y1, and Y2) initiated at different start
codons by a variety of ribosomal gymnastics, including the use of
non-AUG codons, leaky scanning, and shunting (5, 23). We
have previously described rSeV strains which selectively do not express
either their C', C, or C', and C proteins (double mutant), due to
mutation of their respective start codons. The phenotypes of the
C'
and C viruses were similar. They grew
slightly less well than wild-type virus in eggs, and their infections
of BHK cells overaccumulated viral macromolecules, consistent with the
ability of either C' or C (but not Y1 and Y2) to inhibit viral RNA
synthesis (4). Despite these similar phenotypes in eggs and
cell culture, C' virus was as virulent as
rSeVZ for mice, whereas C virus was
avirulent. The double mutant, which in contrast to the single mutants
was relatively noncytopathic in cell culture (and displayed a
small-plaque phenotype), was also avirulent at the highest doses tested
(22).
behaved like
its wild-type control (rSeVZ) (lanes 1 and 2). Fifty hours
of C' infection (lanes 9 and 10) did not induce an
anti-VSV state (lane 9) and prevented the effects of IFN treatment as
well (lane 10), and the levels of Stat1 proteins were not elevated over
background levels (lanes 9 and 10). C infection (lanes 7 and 8), in contrast, and the double mutant infection (lanes 11 and 12)
to an even greater extent did (at least partially) induce an anti-VSV
state and significantly elevated Stat1 levels over background levels.
Thus, the AUG114-initiated C protein (but not C', Y1, or
Y2) is preferentially required to prevent SeV infection from inducing
the IFN system in cell culture, consistent with its specific
requirement for sustained viral replication in the mouse respiratory
tract (22).
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; lanes 7 and 8),
rSeVZ-[C'Suppression of the IFN-mediated anti-VSV state is dominant. Although SeVMVC grows ca. 20-fold better than SeVM in MK2 cells, this virus actually grows ca. 5-fold less well than SeVM in eggs (as well as in BF cells), and these relative replication efficiencies also apply to rSeVZ-CMVC versus rSeVZ-CM. All of our rSeV strains are isolated in hen's eggs, and generally stocks at the 2nd or 3rd passage level (p2 or p3) are used to infect cell cultures. Six rSeVZ-CMVC stocks were originally isolated from DNA independently, and all behaved as shown (Fig. 3) and grew relatively poorly in eggs. On further passage, however, some rSeVZ-CMVC stocks clearly grew better (5- to 10-fold) than others. Because the F170S mutation apparently confers reduced growth in eggs (and the loss of an XmnI site), the relevant region of the viral genomes in two stocks which grew well (p4MVC-118 and p5MVC-1.8) and two which grew poorly (p4MVC-119 and p3MVC-9.9) was amplified and examined (Fig. 5). At the same time, BF cells were infected with the same stocks and superinfected with VSV at 48 hpi as before, to determine whether infection with these stocks continued to induce an anti-VSV state.
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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To sustain its infection of the mouse respiratory tract, SeV must
avoid or counteract the innate immune response of its animal host,
which includes natural killer cells, the IFN system, and PCD. The most
virulent virus strains, like SeVM, must be extremely
efficient at these countermeasures, because they require only ca. 40 PFU to kill half of the mice inoculated intranasally.
SeVMVC, an SeVM mutant with only two amino acid
substitutions (one in the C gene and the other in the catalytic subunit
of the viral polymerase [L]), however, appears to be virtually
defenseless against the innate immune system of the mouse, because lung
titers increase only during the first day of infection, and virus is
then quickly cleared (16). Moreover, similar results were
found for mice infected with rSeVZ-CMVC, a
chimeric Z strain virus containing the mutant SeVMVC C
gene, or rSeVZ-[C], which contains a
wild-type C gene but does not express the AUG114-initiated
C protein. The SeV C gene thus plays a critical role in infections of
its animal host, presumably by counteracting innate immunity.
Itoh et al. (17) have recently found that SeVM infections do not induce PCD either in MK2 cells or in the mouse respiratory tract, whereas SeVMVC infections are highly apoptogenic in both cases. The present work has found that SeVM infection interferes with the IFN-mediated induction of an antiviral state, in strong contrast to SeVMVC. It is possible that SeVM infections counteract the induction of PCD and the antiviral effects of IFN by separate pathways, but it is more likely that these effects are linked. Cells from mice lacking PKR (35) or the 2-5A-oligoadenylate synthetase dependent RNase L (37) show defects in PCD, suggesting a role for these enzymes in virus-induced, IFN-mediated PCD. Furthermore, several viruses have recently been found to induce PCD via activation of the IFN system (31). The Stat1 proteins themselves also induces genes involved in PCD (3, 20, 29), and SeVMVC infection may be highly apoptogenic because it induces high levels of Stat1.
The molecular basis of the antiviral response to IFN is not fully
understood. More than 50 genes are induced by IFN-/, but only a
few of these gene products display intrinsic antiviral activity,
namely, p68 protein kinase (PKR) and 2-5A oligoadenylate synthetase
(both dependent on double-stranded RNA for activity) (18),
certain Mx family proteins (reviewed in reference
30), and, most recently, the promyelocytic leukemia
(PML) protein (2). While IFN-treated cells are resistant to
many different viruses, individual overexpression of these
intrinsically antiviral proteins confers resistance only against some
viruses. Thus, overexpression of PKR or 2-5A oligoadenylate synthetase
confers resistance to the picornavirus encephalomyocarditis virus
(EMCV), but not to the rhabdovirus VSV, whereas overexpression of human
MxA or PML proteins confers resistance to VSV, but not to EMCV
(2). The enormous selective pressures imposed by viruses
have resulted in a rich and diverse set of antiviral pathways, and the
antiviral state induced via the IFN system is thus suitably complex. We have used two criteria
the ability of VSV to replicate following a
period of SeV infection and the intracellular levels of the Stat1
proteinsas indicators of this cellular antiviral state. We have found
that two different mutations in the C gene, the F170S substitution and
the specific loss of AUG114-initiated C protein (although
C' is normally expressed and the Y1 and Y2 proteins are overexpressed),
largely eliminate the ability of the mutant infections to prevent the
IFN-mediated antiviral state. The SeV C gene thus plays a critical role
in this process. The E2050A mutation in the L gene of
SeVMVC also appears to be involved in the attenuation of
this virus, because the phenotype of SeVMVC is consistently
stronger than that of rSeVZ-CMVC, especially in
preventing the elevation of Stat1 proteins, thereby eliminating one
pathway to the induction of PCD.
While this paper was under review, Didcock et al. (8a)
reported that SeV strain H (SeVH, which is very similar to
SeVZ) circumvents the IFN response and does so by
interfering with the transcriptional activation of IFN-responsive
genes. This study used only wild-type SeVH and another
paramyxovirus, SV5. However, it directly examined IFN signaling in BF
cells, using transient transfection of plasmids in which a luciferase
reporter gene was placed under the control of an IFN-/-responsive
promoter (or an IFN- promoter), followed by virus infection. The
IFN-/-responsive promoter was found to be strongly activated in
both mock- and SV5-infected cells treated with IFN, whereas little or
no activation of this promoter was observed in SeV-infected cells. In
contrast, SeV was a stronger inducer of the IFN- promoter than SV5.
These authors concluded that the failure of SeVH-infected
cells to respond to the substantial levels of IFN-/ they produce
was due to the effectiveness of the SeVH-induced block.
SeVM and SeVMVC infections of human peripheral
blood mononuclear cells are found to produce equivalent (and
substantial) amounts of IFN- (3,395 IU/ml for M and 3,776 IU/ml for
MVC) (13b). Thus, all of these wild-type SeV strains
(strains M, Z, and H) presumably counteract the IFN-induced antiviral
state by interfering with the activation of IFN-stimulated genes.
The dominant nature of rSeVZ-CM versus rSeVZ-CMVC in coinfections of eggs (Fig. 5) and BF cells [data not shown] suggests that the C gene actively interferes with the induction of the antiviral state rather than simply avoiding the induction, although it might do this as well. We have not as yet examined whether the C gene products can act in BF cells independent of virus infection. The C proteins might well interact with directly (and suppress) some component of the signaling pathway leading to an antiviral state, because many viruses are known to subvert the IFN system by a wide variety of mechanisms (30). The apparent enhancing effect of the polymerase LE2050A mutation in viruses with CF170S (SeVMVC), however, suggests that the C proteins act as well via viral RNA synthesis. C is well placed to do this. The linear paramyxovirus genomes and antigenomes contain promoters for RNA synthesis at their 3' ends. The C protein acts as an inhibitor of viral RNA synthesis in a promoter-specific fashion (1, 32); i.e., it predominantly inhibits antigenome and mRNA synthesis from the genomic promoter. This inhibition depends on the relative ratio of C protein to genomes, which increases dramatically during the early stages of infection, because C protein is essentially a nonstructural protein.
The SeV V protein is also known to affect viral RNA synthesis
(3a). However, in contrast to rSeV-[C],
infection of BF cells with two different rSeV strains which cannot edit
their P gene mRNA and do not express V (
6A [7] and
A5G3 [13a]) was similar to that of wild-type virus.
These rSeV-[edit] infections did not induce an anti-VSV
state, and they continued to prevent IFN (added concomitant with the
infection) from inducing an anti-VSV state (data not shown). The SeV V
protein therefore does not appear to be important in counteracting IFN
action, although it is also thought to function in counteracting some
aspect of innate immunity (19). The SeV C and V proteins
have been referred to as "accessory" proteins, in the sense that
they are not expressed by all paramyxoviruses. For example, human
parainfluenza virus type 1, the virus closest to SeV and a very
successful parasite of children, does not contain a V open reading
frame (ORF) at all (25), and rubulaviruses (except for
Newcastle disease virus) do not contain a C ORF. The overlapping C and
V ORFs appear to have been added to the P ORF as a late event of virus
evolution, possibly to adapt these viruses to a particular ecological
niche (e.g., the mouse respiratory tract). The V gene clearly fits this description, providing a "luxury" function (19), because
rSeV strains which do not express V are perfectly competent for growth in cell culture or eggs and are only debilitated for growth in the
mouse respiratory tract (7, 8, 19).
The C gene is more complex than the V gene. There are four independently initiated C proteins, and the phenotypes of viruses in which C' and C have been specifically ablated suggest that the various C proteins must, at least in part, have nonoverlapping functions. While rSeV strains which cannot individually express C' or C grow well in (IFN-incompetent) BHK cells and accumulate viral macromolecules more rapidly than wild-type virus, the double mutant (which cannot express either C' or C) grows poorly in BHK cells and accumulates viral macromolecules with delayed kinetics relative to wild-type virus. C' and C (but not Y1 or Y2) may provide a common function that accelerates the accumulation of viral products intracellularly, so that only the double mutant shows the loss-of-function phenotype (22). C' and C also appear to have nonoverlapping functions, because although C or Y1 and Y2 can replace C' for virulence in mice, C' or Y1 and Y2 cannot replace C for this property (22). Y1 and Y2 presumably also play a role in intracellular virus replication, because rSeV strains which cannot express any of their C proteins have not been isolated (22), and those which at best express only some Y2 protein are at the limit of recovery from DNA (21, 23). Unlike the V gene, the SeV C gene clearly plays an essential role in intracellular virus replication, even in the protected environment of defenseless cells in culture. What may have started out as a luxury function could have evolved to carry out essential functions in virus replication. Multiple forms of C protein expression may then have evolved to better regulate their function.
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ACKNOWLEDGMENTS |
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We thank Angelica Hopkins for excellent technical assistance; Rick Randall (Aberdeen) for introducing us to IFN-competent BF cells; and J. Perrault (San Diego), D. Summers (NIH), L. Roux (Geneva), C. Orvell (Stockholm), G. Gabbiani (Geneva), and Y. Nagai (Tokyo) for their generous gifts of antibodies.
This work was supported by a grant from the Swiss National Science Fund.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Genetics and Microbiology, University of Geneva School of Medicine, CMU, 9 Ave. de Champel, CH1211 Geneva, Switzerland. Phone: (4122) 702 5657. Fax: (41 22) 702 5702. E-mail: Daniel.Kolakofsky{at}Medecine.unige.ch.
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REFERENCES |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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