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-Stimulated Antiviral and Immunoregulatory Responses by Blocking Multiple Levels of IFN- Signal Transduction1
Department of Pathology, Ohio State University, Columbus, OH 43210
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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confers resistance to
viral infection by activating a conserved signal transduction pathway
that up-regulates direct antiviral effectors and induces
immunomodulatory activities. Given the critical role of IFN- in
anti-human cytomegalovirus (HCMV) immunity and the profound ability
of HCMV to escape the host immune response, we hypothesized that HCMV
blocks IFN--stimulated responses by disrupting multiple levels of
the IFN- signal transduction pathway. We demonstrate that HCMV
inhibits IFN--stimulated MHC class I, IFN regulatory factor-1, MxA
and 2',5-oligoadenylate synthetase gene expression, transcription
factor activation, and signaling in infected fibroblasts and
endothelial cells by decreasing the expression of Janus kinase 1 and
p48, two essential components of the IFN- signal transduction
pathway. This investigation is the first to report inhibition of type I
IFN signaling by a herpesvirus. We propose that this novel immune
escape mechanism is a major means by which HCMV is capable of escaping
host immunity and establishing persistence. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The type I IFNs, a multigene family of multiple IFN- subtypes and a
single IFN-ß, represent a primordial, tightly regulated defense
system against acute viral infection (8). IFN- confers resistance to
viral infection by up-regulating direct antiviral effectors, such as
2',5'-oligoadenylate synthetase (2',5'-OAS) and Mx proteins, and
inducing immunomodulatory activities, including up-regulation of IFN
regulatory factor-1 (IRF-1) and MHC class I expression (8, 9).
High levels of type I IFNs are produced early after CMV infection and
are critical in limiting CMV replication and associated mortality. Mice
injected with blocking Abs to IFN- during acute CMV infection
develop higher CMV titers (10), and IFN- treatment decreases CMV
replication in vivo (11, 12). Furthermore, IFN- receptor knockout
mice are 800-fold more susceptible to acute CMV-induced mortality than
wild-type mice (13).
The diverse biological activities of the type I IFNs are mediated by a
conserved signal transduction pathway (9, 14). Following binding of
IFN- to its receptor, a heterodimer consisting of IFN- receptor 1
(IFNAR1) and IFNAR2 (15), there is activation and tyrosine
phosphorylation of Janus kinase (Jak)1 and Tyk2 receptor-associated
kinases. Once phosphorylated, Jak1 and Tyk2 tyrosine phosphorylate
IFNAR1, Stat2, and Stat1 (9, 16). Phosphorylated Stat1 and Stat2
molecules form a heterodimer that unites with p48, a DNA-binding
protein, to form a transcription factor complex known as IFN-stimulated
gene factor 3 (ISGF3) (17, 18). ISGF3 translocates to the nucleus to
activate transcription by binding to IFN-stimulated response elements
(ISRE) in the promoters of many IFN- responsive genes (9).
Although many IFN--stimulated genes are transcriptionally regulated
by ISGF3/ISRE interactions, there is evidence that several of these
genes are induced by factors other than ISGF3 (19). Stat1/Stat2
heterodimers and Stat1 homodimers are capable of transactivating
IFN--stimulated genes independent of the p48 component of ISGF3 by
binding to promoter elements such as the inverted repeat (IR) element
of IRF-1 (20).
We have previously described an HCMV-specific decrease in Jak1, an
obligatory component of type I IFN signaling, that is associated with a
block in IFN-
signal transduction (21). However, it has recently
been reported that a constituent of the HCMV virus particle,
independent of the IFN signal transduction pathway, up-regulates a
subset of IFN- responsive genes (22). The authors propose that HCMV
is not capable of blocking IFN responsiveness, as is the case for the
adenovirus E1A gene product (22, 23, 24, 25). Therefore, we tested the
hypothesis that the HCMV-associated decrease in Jak1 is associated with
inhibition of IFN--stimulated gene expression, transcription factor
activation, and signal transduction within infected human fibroblasts
and endothelial cells (ECs). Herein we demonstrate that there are
multiple HCMV-associated lesions in the IFN- signal transduction
pathway analogous to the multiple levels at which HCMV targets MHC
class I expression (26).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human umbilical vein ECs were isolated from vessels and
propagated as previously described (27). ECs were infected with HCMV
strain VHL/E (28). HCMV-infected ECs were generated by a dispersion
method that yields a culture of >95% infected ECs (27). Human
embryonic lung fibroblasts (MRC-5), passages 22–35, were cultured in
Eagle’s minimal essential medium supplemented with 10% FBS (Life
Technologies, Gaithersburg, MD) at 37°C in a 5% CO2
incubator. HCMV Towne strain was propagated in MRC-5 at low
multiplicity of infection (MOI) with aliquots frozen at -80°C and
titer determined as described elsewhere (29). In all experiments, Towne
HCMV was incubated with fibroblasts at an MOI of 7. To inhibit HCMV
late gene expression, cells were infected with Towne in the presence of
300 µg/ml phosphonoformic acid (PFA; Sigma, St. Louis, MO). Human
IFN- (PeproTech, Rocky Hill, NJ) was used as described for each
experiment.
Northern blot analysis
A total of 10 µg of total cytoplasmic RNA, isolated by guanidium thiocyanate extraction and cesium chloride centrifugation, was separated on a 1.4% agarose/0.22 M formaldehyde gel and transferred to nylon membranes (Hybond-N; Amersham, Arlington Heights, IL). For p48 mRNA blots, mRNA from 3 x 107 fibroblasts and ECs was isolated (Invitrogen, Carlsbad, CA) and fractionated as above. Random priming (DecaPrime II Kit; Ambion, Austin, TX) of GAPDH, p48 (30), and HLA-B7 probes was performed (27). Reaction products were purified from unincorporated isotope via a Mini Spin G-50 column (Worthington Biochemicals, Lakewood, NJ), melted, hybridized, and detected as described (27). Following hybridization overnight at 42°C, the final wash was conducted at 56°C with 0.2x SSC and 0.1% SDS for 30 min. Autoradiography was performed with XAR film (Kodak, Rochester, NY) at -80°C.
RT-PCR
A total of 10 µg of cytoplasmic RNA was treated with 10U RNase-free DNase (Stratagene, La Jolla, CA) for 30 min at 37°C followed by phenol/chloroform extraction and ethanol precipitation at -80°C. Samples were reverse transcribed (Life Technologies; no. 18064-014), and one 5 µg aliquot for each sample served as a non-RT control to control for genomic contamination in subsequent PCR reactions. Following heating at 94°C for 3 min, the reaction mixture was cycled: 1 min at 94°C, 2 min at 55°C, 3 min at 72°C, and a final 10-min elongation step at 72°C. PCR reactions were performed with ß-actin (540-bp PCR product), MxA (605-bp PCR product), and OAS primers (621-bp PCR product), and products were analyzed on ethidium bromide-stained 2% agarose gels. All PCR products were cloned into pCRII vector (Invitrogen) and sequenced by the dideoxy chain termination method. Primer sets are as follows: ß-actin primers are as described previously (21); MxA sense 5'-CATACTGCGAGGAGATCGGTTC-3' and MxA antisense, 5'-AGCATCCGAAATCTCAATCTCGTA-3'; OAS sense 5'-AGAATGTCAGACACTGATCGACGA-3' and OAS antisense 5'-TGTTCCCAGGCATACACCGTA-3'.
EMSA
Nuclear extracts were prepared by a modification of the methods
previously described (31). A total of 5 µg of nuclear extract was
combined with 2 µl of 5x binding buffer, 2 µl of poly(dI-dC), and
2 µl of 32P-labeled IR element probe (20). The reaction
was incubated at room temperature for 20 min and resolved on a 4.5%
nondissociating polyacrylamide gel. For controls, 1 µl (100 ng) of
100x cold IR element probe, 1 µl of Stat1 pAb, 1 µl of Stat2
pAb, or 1 µl of p48 pAb (all from Santa Cruz Biotechnology, Santa
Cruz, CA) was added to the binding reaction before the addition of
radiolabeled probe for competition and supershift assays, respectively.
Immunoprecipitation (IP)
IP was performed as previously described (21). For Stat1,
Stat2, and IFNAR-1 IP, 10 x 106 cells per treatment
were lysed in IP lysis buffer consisting of 1% Triton X-100, 0.15 M
NaCl, 50 mM Tris (pH 8.0), 50 mM NaF, 5 mM sodium pyrophosphate, 1 mM
PMSF, 1 mM orthovanadate, and 5 µg/ml each of pepstatin, leupeptin,
and aprotinin. For Jak1 and Tyk2 IP, 20 x 106 cells
per treatment were solubilized in IP lysis buffer. Postnuclear lysates
were precleared overnight at 4°C with rabbit Ig (Pharmacia,
Piscataway, NJ) and protein A-Sepharose (Pharmacia). Nonspecific rabbit
Ig complexes were pelleted by centrifugation, and precleared lysates
were incubated at 4°C with Stat1, Stat2, IFNAR-1, Jak1, or Tyk2
pAb (all from Santa Cruz Biotechnology) and excess protein A-Sepharose.
Immune complexes were collected and fractionated under reducing
conditions on 7.5% SDS-PAGE. Following transfer of proteins to
nitrocellulose (Micron Separations, Westborough, MA), Western blots
were incubated with anti-Stat1, -Stat2, -IFNAR-1, -Jak1, -Tyk2,
or -phosphotyrosine Abs (HRP-conjugated Ab; Transduction, Lexington,
KY) at 1:1000, either at 4°C overnight or at room temperature for
2 h. Blots were washed with TBS-Tween for 1 h, incubated with
anti-rabbit IgG-HRP (1:3000; Santa Cruz Biotechnology), washed
again with TBS-Tween, and developed utilizing Ultrachemiluminescence
(Pierce, Rockford, IL).
Western blot analysis
Fibroblasts and ECs were lysed in 5% SDS, 0.5 M Tris HCl (pH 6.8), and 0.5 mM EDTA, with protease inhibitors. Following centrifugation at 15,000 rpm for 15 min, equal volumes of lysate from an equivalent number of cells were fractionated by 7.5% SDS-PAGE (Stat1, Stat2, Jak1) or 10% SDS-PAGE (p48) under reducing conditions. Following trasfer to nitrocellulose, blots were probed with 1:1000 anti-p48 pAb (Santa Cruz Biotechnology) at 4°C overnight. Blots were washed with TBS-Tween for 1 h, incubated with anti-rabbit IgG-HRP (1:3000, Santa Cruz), washed again with TBS-Tween, and developed utilizing Ultrachemiluminescence (Pierce). pp65 Western blot analysis was performed according to established protocols, and the anti-pp65 Ab was the generous gift of Dr. William Britt (Department of Pediatrics, University of Alabama, Birmingham, AL).
Supernatant transfer assay
Supernatants were prepared from HCMV-infected fibroblast
cultures as previously described (32). Briefly, at 72 h
postinfection, 3 ml of supernatant from mock-infected or HCMV-infected
fibroblast cultures was spun at 100,000 x g for 30
min. This cleared supernatant was added to noninfected fibroblast
cultures for 24 h. Cells incubated with either mock-infected or
HCMV-infected supernatants were then stimulated with 1500 U/ml IFN-
for 30 min. Nuclear extracts were recovered, and EMSA was performed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-stimulated gene expression
We utilized human ECs and fibroblasts, targets of HCMV infection
in vivo, to investigate the effect of HCMV on IFN--stimulated
cellular responses (33, 34). ECs were infected with VHL/E, an EC-tropic
clinical isolate, and fibroblasts with a common laboratory strain of
HCMV, Towne.
MHC class I expression is regulated primarily at the transcriptional
level in vivo (35). IFN- up-regulates MHC class I expression through
ISGF3/ISRE interactions within the IFN consensus sequence of MHC class
I promoters (36, 37). We analyzed the ability of IFN- to up-regulate
MHC class I expression in HCMV-infected fibroblasts and ECs by Northern
blot analysis of HLA-B7 induction. IFN- up-regulated HLA-B7
expression to levels consistent with previous reports, 
2-fold in
noninfected fibroblasts and 3-fold in noninfected ECs (Fig. 1
A) (38). However, there was
no significant induction of HLA-B7 RNA in HCMV-infected fibroblasts and
ECs (Fig. 1A).
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induces an antiviral state, in part, through the effects of the
antiviral effectors 2',5'-OAS and MxA. Although MxA and 2',5'-OAS have
antiviral activity against RNA viruses and their contribution to the
IFN--stimulated inhibition of herpesvirus replication is not clear,
they are utilized here as an indicator of IFN--stimulated gene
expression (39, 40). It is believed that ISGF3/ISRE interactions
mediate the IFN--stimulated expression of the 2',5'-OAS and MxA
genes (41, 42). The expression of IRF-1, an IFN--stimulated gene
that is not regulated by ISGF3/ISRE interactions, was also
investigated. Two lines of evidence demonstrate that the IRF-1 gene is
up-regulated by IFN- in the absence of ISGF3/ISRE interactions.
First, the IRF-1 promoter does not contain an ISRE site but rather the
IR element, which binds Stat1 homodimers and Stat1/Stat2 heterodimers
but not ISGF3 (20). Second, IFN- stimulates IRF-1 expression in cell
lines lacking the p48 subunit of ISGF3 (20). IRF-1 expression was
investigated to determine whether IFN--stimulated ISGF3-independent
gene expression was blocked as well.
RT-PCR experiments demonstrated a modest increase in the constitutive
levels of IRF-1 and MxA in HCMV-infected fibroblasts, but not within
infected ECs (Fig. 1
B, lane 1 vs lane
3). In our analysis of IFN--stimulated gene expression, RT-PCR
experiments demonstrated that IFN- up-regulated the expression of
IRF-1, 2',5'-OAS, and MxA in noninfected fibroblasts and ECs (Fig. 1B, lane 1 vs lane 2), but there was
no induction of these genes with IFN- treatment in HCMV-infected
cells (Fig. 1B, lane 3 vs lane 4).
HCMV inhibits IFN--stimulated signal transduction
EMSAs were used to determine whether the HCMV block of
IFN--stimulated gene expression was due to an inability to form
ISGF3 or Stat1 homodimers. In EMSA experiments utilizing a
32P-labeled ISRE probe, we could not detect ISGF3 complexes
in control experiments in fibroblasts and ECs. We found that, in
fibroblasts and ECs, the amount of p48 protein was limiting (data not
shown). Moreover, HCMV-infected cells were found to be refractory to
IFN--stimulated up-regulation of p48 expression (data not shown),
which is frequently required for ISGF3 formation (43, 44). Therefore,
the ability of IFN- to stimulate the formation of Stat1 homodimers
was tested by EMSA experiments utilizing the IR element of the IRF-1
promoter as a probe.
The IR element binds IFN- stimulated Stat1 homodimers that are
capable of up-regulating the transcription of the IRF-1 gene (20).
IFN- stimulated Stat1 homodimer formation in noninfected fibroblasts
and ECs but not in HCMV-infected cells (Fig. 2A). Supershift analysis with
Abs to Stat1 verified that the IR probe binds Stat1 homodimers, and no
supershifting of the band was seen with Abs to Stat2 or p48.
Competition experiments with 100-fold excess unlabeled IR element and a
nonspecific control element further confirmed the specificity of the
band.
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-stimulated
Stat1 activation resulted from a soluble factor released into the
supernatant of HCMV-infected cultures, supernatant transfer experiments
were performed. In these assays, supernatants from mock-infected or
HCMV-infected fibroblast cultures were cleared of virus and transferred
to noninfected fibroblasts. Following a 24-h incubation with the
transferred supernatants, fibroblasts were treated with IFN-, and
EMSA was performed utilizing the IR probe. Supernatants from
mock-infected and HCMV-infected fibroblasts had no effect on
IFN--stimulated Stat1 homodimer formation (Fig. 2B).
We investigated IFN- signal transduction in HCMV-infected cells by
IP. Noninfected and HCMV-infected fibroblasts were treated with
IFN-, followed by IP of IFNAR-1, Stat2, Stat1, Jak1, and Tyk2.
Western blot analysis with an anti-phosphotyrosine Ab demonstrated
that IFN- stimulated the phosphorylation of these proteins in
noninfected cells but not in HCMV-infected cells (Fig. 3A). Western blot analysis of
the levels of expression of the immunoprecipitated proteins revealed no
change in the relative levels of expression of IFNAR-1, Stat2, and
Stat1 and a slight increase in Tyk2 in HCMV-infected cells (Fig. 3B). However, there was a significant decrease of Jak1
protein in infected cells, as previously described (Fig. 3B)
(21).
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The ISGF3 complex consists of p48, the DNA binding component, as
well as Stat1 and Stat2. p48 is not phosphorylated in response to
IFN-, rather it associates with phosphorylated Stat1/Stat2
heterodimers to form ISGF3, which binds to ISRE elements in the
promoters of many IFN--responsive genes (14, 43). Western blot
analysis revealed that p48 was detectable in lysates from noninfected
fibroblasts and ECs but not in HCMV-infected cells (Fig. 4A). The specificity of the
anti-p48 Ab was confirmed by the lack of p48 immunoreactivity in
the presence of a purified p48 peptide, the absence of reactivity in
the p48 negative cell line U2A, and the presence of p48
immunoreactivity in the p48 positive cell line U2A/p48 (Fig. 4B).
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A). This
experiment suggests that p48 is decreased in HCMV-infected cells by a
posttranscriptional mechanism. Analyses of p48 protein levels in
HCMV-infected cells by Western blot analysis at varying times after
infection revealed a decrease in p48 protein levels between 24 and
48 h after HCMV infection, and the protein was not detectable by
72 h (Fig. 5B).
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demonstrates that p48
expression is decreased in PFA-treated HCMV-infected cells, suggesting
that HCMV genes expressed in the early phase (i.e., not dependent upon
the activity of the HCMV DNA polymerase) mediate the decrease in p48
protein levels.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-stimulated
signal transduction and gene expression, and 2) HCMV induces lesions at
multiple levels of the IFN- signal transduction pathway.
Specifically, we found that IFN--stimulated ISGF3-dependent and
ISGF3-independent gene expression, including 2',5'-OAS, MxA, IRF-1, and
MHC class I expression, was inhibited in HCMV-infected fibroblasts and
ECs. These studies also demonstrate, for the first time, that HCMV
infection is associated with marked decreases in p48 protein levels,
which appear to be secondary to HCMV immediate early or early gene
products.
There is significant data demonstrating that IFN- activates genes,
such as IRF-1, independent of the p48 component of the ISGF3 complex
(19, 20). Therefore, we propose that the decrease of Jak1 expression
inhibits IFN--stimulated ISGF3-independent gene expression (Fig. 7). p48 is the principal mediator of
ISGF3 binding to ISRE DNA elements present within IFN- promoters
(43). Studies in p48 negative cell lines and in p48 knockout mice
demonstrate that IFN--stimulated ISGF3-dependent gene expression is
inhibited in cells lacking p48 (45). Moreover, investigations in p48
knockout mice show that p48 is critical to the establishment of
IFN-- and IFN--induced antiviral states (45). Thus, we propose a
model in which the HCMV-associated decrease in p48 expression, combined
with the absence of Stat1 and Stat2 phosphorylation secondary to
decreased Jak1, blocks IFN--stimulated ISGF3-dependent gene
expression (Fig. 7).
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B,
we detected increases in the constitutive levels of IRF-1 and MxA RNA
in HCMV-infected fibroblasts. This increase in constitutive levels did
not occur in infected ECs, suggesting that there may be cell
type-specific responses to HCMV (Fig. 1B).
As a result of the finding that HCMV up-regulates a subset of
IFN-responsive genes, it has been proposed that HCMV is not capable of
blocking IFN responsiveness, as is the case for the adenovirus E1A gene
product (22, 23, 24, 25). However, this study, which directly tests the
hypothesis that HCMV infection disrupts IFN--stimulated responses,
demonstrates that infection does interfere with IFN--stimulated MHC
class I, IRF-1, MxA, and 2',5'-OAS gene expression, transcription
factor activation, and signaling in infected fibroblasts and ECs.
In concert with studies of other virus infections, these studies
suggest that viral disruption of IFN-stimulated responses may be
important to viral replication. Although HCMV is the only herpesvirus
known to block type I IFN signaling, EBV has been shown to block type I
IFN gene expression through a mechanism downstream of the formation of
ISGF3 and its binding to the ISRE element (46). Adenovirus E1A gene
products have been shown to inhibit type I IFN responses by decreasing
p48 and Stat1, but the mechanisms underlying these decreases are
unknown (23, 25). In contrast to HCMV, adenovirus E1A does not appear
to be associated with a decrease in Jak1 (25). Recently, it was
discovered that HCMV selectively up-regulates the expression of the
IFN--responsive ISG54 gene by a mechanism not dependent upon IFN-
signal transduction, but rather through the action of a novel
HCMV-induced ISRE-binding factor (47). Evidence that this mechanism
operated outside of the classic IFN- pathway included the finding
that HCMV infection did not initiate the assembly of Stat1, Stat2, and
p48 into the ISGF3 complex and did not result in nuclear translocation
of Stat1. Thus, while HCMV inhibits IFN signal transduction through the
Jak/Stat pathway, there may be activation of a subset of IFN-responsive
genes by Jak/Stat-independent mechanisms.
Both ECs and fibroblasts were examined because they represent frequent yet phenotypically distinct targets of HCMV infection in vivo (33, 34). ECs play a particularly important role in CMV pathobiology, serving as reservoirs of persistent virus as well as critical intermediates in the HCMV dissemination pathway (48, 49, 50). ECs are an essential component of the inflammatory response, due to their boundary location between the blood and tissue and constant exposure to circulating leukocytes. They are highly responsive to multiple cytokines and can be induced to function as "semiprofessional" APCs (51, 52). Thus, in order for ECs to serve as reservoirs of infection, it is critical that HCMV protect infected cells from type I IFN-stimulated antiviral and immunoregulatory responses.
In conclusion, we have discovered that HCMV blocks IFN--stimulated
antiviral and immunoregulatory activity through inhibition of both
ISGF3-dependent and ISGF3-independent IFN--stimulated gene
expression associated with specific decreases in p48 and Jak1 levels.
The finding that HCMV creates multiple lesions in the IFN- signal
transduction pathway, analogous to the multiple levels at which HCMV
blocks the MHC class I Ag presentation pathway (26), suggests that
disruption of IFN- signal transduction is critical to HCMV
replication and persistence. These findings support an evolving
paradigm of viral persistence wherein viruses, through inhibition of
signal transduction, globally block IFN-stimulated antiviral and
immunoregulatory responses within infected cells.
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Acknowledgments |
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Footnotes |
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2 D.M.M. was a Howard Hughes Medical Institute Predoctoral Fellow.
3 Address correspondence and reprint requests to Dr. Daniel D. Sedmak, 139 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. E-mail address:
4 Abbreviations used in this paper: HCMV, human cytomegalovirus; 2',5'-OAS, 2',5' oligoadenylate synthetase; IRF-1, IFN regulatory factor-1; Jak, Janus kinase; ISGF3, IFN-stimulated gene factor 3; ISRE, IFN-stimulated response element; IR, inverted repeat; EC, endothelial cell; PFA, phosphonoformic acid; IP, immunoprecipitation; IFNAR, IFN- receptor 1.
Received for publication November 9, 1998. Accepted for publication February 19, 1999.
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S. M. Best, K. L. Morris, J. G. Shannon, S. J. Robertson, D. N. Mitzel, G. S. Park, E. Boer, J. B. Wolfinbarger, and M. E. Bloom Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist J. Virol., October 15, 2005; 79(20): 12828 - 12839. [Abstract] [Full Text] [PDF]
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 A. Zimmermann, M. Trilling, M. Wagner, M. Wilborn, I. Bubic, S. Jonjic, U. Koszinowski, and H. Hengel A cytomegaloviral protein reveals a dual role for STAT2 in IFN-{gamma} signaling and antiviral responses J. Exp. Med., May 16, 2005; 201(10): 1543 - 1553. [Abstract] [Full Text] [PDF]
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S. Yang, J. Netterwald, W. Wang, and H. Zhu Characterization of the Elements and Proteins Responsible for Interferon-Stimulated Gene Induction by Human Cytomegalovirus J. Virol., April 15, 2005; 79(8): 5027 - 5034. [Abstract] [Full Text] [PDF]
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J. Netterwald, S. Yang, W. Wang, S. Ghanny, M. Cody, P. Soteropoulos, B. Tian, W. Dunn, F. Liu, and H. Zhu Two Gamma Interferon-Activated Site-Like Elements in the Human Cytomegalovirus Major Immediate-Early Promoter/Enhancer Are Important for Viral Replication J. Virol., April 15, 2005; 79(8): 5035 - 5046. [Abstract] [Full Text] [PDF]
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T. Kubota, N. Yokosawa, S.-i. Yokota, N. Fujii, M. Tashiro, and A. Kato Mumps Virus V Protein Antagonizes Interferon without the Complete Degradation of STAT1 J. Virol., April 1, 2005; 79(7): 4451 - 4459. [Abstract] [Full Text] [PDF]
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D. A. Abate, S. Watanabe, and E. S. Mocarski Major Human Cytomegalovirus Structural Protein pp65 (ppUL83) Prevents Interferon Response Factor 3 Activation in the Interferon Response J. Virol., October 15, 2004; 78(20): 10995 - 11006. [Abstract] [Full Text] [PDF]
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R.-J. Lin, C.-L. Liao, E. Lin, and Y.-L. Lin Blocking of the Alpha Interferon-Induced Jak-Stat Signaling Pathway by Japanese Encephalitis Virus Infection J. Virol., September 1, 2004; 78(17): 9285 - 9294. [Abstract] [Full Text] [PDF]
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S.-i. Yokota, N. Yokosawa, T. Okabayashi, T. Suzutani, S. Miura, K. Jimbow, and N. Fujii Induction of Suppressor of Cytokine Signaling-3 by Herpes Simplex Virus Type 1 Contributes to Inhibition of the Interferon Signaling Pathway J. Virol., June 15, 2004; 78(12): 6282 - 6286. [Abstract] [Full Text] [PDF]
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A. V. Chee and B. Roizman Herpes Simplex Virus 1 Gene Products Occlude the Interferon Signaling Pathway at Multiple Sites J. Virol., April 15, 2004; 78(8): 4185 - 4196. [Abstract] [Full Text] [PDF]
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J. Eickhoff, M. Hanke, M. Stein-Gerlach, T. P. Kiang, K. Herzberger, P. Habenberger, S. Muller, B. Klebl, M. Marschall, T. Stamminger, et al. RICK Activates a NF-{kappa}B-dependent Anti-human Cytomegalovirus Response J. Biol. Chem., March 5, 2004; 279(10): 9642 - 9652. [Abstract] [Full Text] [PDF]
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L. Pereira, E. Maidji, S. McDonagh, O. Genbacev, and S. Fisher Human Cytomegalovirus Transmission from the Uterus to the Placenta Correlates with the Presence of Pathogenic Bacteria and Maternal Immunity J. Virol., December 15, 2003; 77(24): 13301 - 13314. [Abstract] [Full Text] [PDF]
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 E. P. Browne and T. Shenk Human cytomegalovirus UL83-coded pp65 virion protein inhibits antiviral gene expression in infected cells PNAS, September 30, 2003; 100(20): 11439 - 11444. [Abstract] [Full Text] [PDF]
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M. Fernandez, J. A. Quiroga, and V. Carreno Hepatitis B virus downregulates the human interferon-inducible MxA promoter through direct interaction of precore/core proteins J. Gen. Virol., August 1, 2003; 84(8): 2073 - 2082. [Abstract] [Full Text] [PDF]
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J. Odeberg, B. Plachter, L. Branden, and C. Soderberg-Naucler Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR {alpha}-chain Blood, June 15, 2003; 101(12): 4870 - 4877. [Abstract] [Full Text] [PDF]
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J. Odeberg, H. Browne, S. Metkar, C. J. Froelich, L. Branden, D. Cosman, and C. Soderberg-Naucler The Human Cytomegalovirus Protein UL16 Mediates Increased Resistance to Natural Killer Cell Cytotoxicity through Resistance to Cytolytic Proteins J. Virol., April 15, 2003; 77(8): 4539 - 4545. [Abstract] [Full Text] [PDF]
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T. Compton, E. A. Kurt-Jones, K. W. Boehme, J. Belko, E. Latz, D. T. Golenbock, and R. W. Finberg Human Cytomegalovirus Activates Inflammatory Cytokine Responses via CD14 and Toll-Like Receptor 2 J. Virol., April 15, 2003; 77(8): 4588 - 4596. [Abstract] [Full Text] [PDF]
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M. S. Chevalier, G. M. Daniels, and D. C. Johnson Binding of Human Cytomegalovirus US2 to Major Histocompatibility Complex Class I and II Proteins Is Not Sufficient for Their Degradation J. Virol., July 17, 2002; 76(16): 8265 - 8275. [Abstract] [Full Text] [PDF]
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E. P. Browne, B. Wing, D. Coleman, and T. Shenk Altered Cellular mRNA Levels in Human Cytomegalovirus-Infected Fibroblasts: Viral Block to the Accumulation of Antiviral mRNAs J. Virol., December 15, 2001; 75(24): 12319 - 12330. [Abstract] [Full Text] [PDF]
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L. Terstegen, P. Gatsios, S. Ludwig, S. Pleschka, W. Jahnen-Dechent, P. C. Heinrich, and L. Graeve The Vesicular Stomatitis Virus Matrix Protein Inhibits Glycoprotein 130-Dependent STAT Activation J. Immunol., November 1, 2001; 167(9): 5209 - 5216. [Abstract] [Full Text] [PDF]
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C. M. Preston, A. N. Harman, and M. J. Nicholl Activation of Interferon Response Factor-3 in Human Cells Infected with Herpes Simplex Virus Type 1 or Human Cytomegalovirus J. Virol., October 1, 2001; 75(19): 8909 - 8916. [Abstract] [Full Text] [PDF]
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B. H. Song, G. C. Lee, M. S. Moon, Y. H. Cho, and C. H. Lee Human cytomegalovirus binding to heparan sulfate proteoglycans on the cell surface and/or entry stimulates the expression of human leukocyte antigen class I J. Gen. Virol., October 1, 2001; 82(10): 2405 - 2413. [Abstract] [Full Text] [PDF]
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J. Odeberg and C. Söderberg-Nauclér Reduced Expression of HLA Class II Molecules and Interleukin-10- and Transforming Growth Factor {beta}1-Independent Suppression of T-Cell Proliferation in Human Cytomegalovirus-Infected Macrophage Cultures J. Virol., June 1, 2001; 75(11): 5174 - 5181. [Abstract] [Full Text]
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K. A. Simmen, J. Singh, B. G. M. Luukkonen, M. Lopper, A. Bittner, N. E. Miller, M. R. Jackson, T. Compton, and K. Fruh Global modulation of cellular transcription by human cytomegalovirus is initiated by viral glycoprotein B PNAS, May 30, 2001; (2001) 121177598. [Abstract] [Full Text] [PDF]
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S. Barcy and L. Corey Herpes Simplex Inhibits the Capacity of Lymphoblastoid B Cell Lines to Stimulate CD4+ T Cells J. Immunol., May 15, 2001; 166(10): 6242 - 6249. [Abstract] [Full Text] [PDF]
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R. M. Presti, D. L. Popkin, M. Connick, S. Paetzold, and H. W. Virgin , IV Novel Cell Type-specific Antiviral Mechanism of Interferon {{gamma}} Action in Macrophages J. Exp. Med., February 20, 2001; 193(4): 483 - 496. [Abstract] [Full Text] [PDF]
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S. Goodbourn, L. Didcock, and R. E. Randall Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures J. Gen. Virol., October 1, 2000; 81(10): 2341 - 2364. [Full Text]
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T. Komatsu, K. Takeuchi, J. Yokoo, Y. Tanaka, and B. Gotoh Sendai Virus Blocks Alpha Interferon Signaling to Signal Transducers and Activators of Transcription J. Virol., March 1, 2000; 74(5): 2477 - 2480. [Abstract] [Full Text]
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K. L. Mossman, H. A. Saffran, and J. R. Smiley Herpes Simplex Virus ICP0 Mutants Are Hypersensitive to Interferon J. Virol., February 15, 2000; 74(4): 2052 - 2056. [Abstract] [Full Text]
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K. A. Simmen, J. Singh, B. G. M. Luukkonen, M. Lopper, A. Bittner, N. E. Miller, M. R. Jackson, T. Compton, and K. Fruh Global modulation of cellular transcription by human cytomegalovirus is initiated by viral glycoprotein B PNAS, June 19, 2001; 98(13): 7140 - 7145. [Abstract] [Full Text] [PDF]
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