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Microbiology and Molecular Biology Reviews, March 2001, p. 131-150, Vol. 65, No. 1
Department of Medical Microbiology and
Immunology, University of Aarhus, DK-8000 Aarhus C, Denmark
1092-2172/01/$04.00+0 DOI: 10.1128/MMBR.65.1.131-150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Molecular Pathways in Virus-Induced Cytokine
Production
SUMMARY
INTRODUCTION
VIRUS-INDUCED SIGNAL TRANSDUCTION AND CYTOKINE EXPRESSION
Herpes Simplex Virus
Cytomegalovirus
Epstein-Barr Virus
Influenza Virus
Hepatitis B Virus
Human Immunodeficiency Virus
Human T-Lymphotropic Virus Type 1
EXPERIMENTAL MODELS FOR VIRAL INFECTIONS
CONCLUDING REMARKS
ACKNOWLEDGMENTS
REFERENCES
SUMMARY
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Virus infections induce a proinflammatory response including expression of cytokines and chemokines. The subsequent leukocyte recruitment and antiviral effector functions contribute to the first line of defense against viruses. The molecular virus-cell interactions initiating these events have been studied intensively, and it appears that viral surface glycoproteins, double-stranded RNA, and intracellular viral proteins all have the capacity to activate signal transduction pathways leading to the expression of cytokines and chemokines. The signaling pathways activated by viral infections include the major proinflammatory pathways, with the transcription factor NF-
B having received special attention. These transcription factors in turn promote the expression of specific inducible host proteins and participate in the expression of some viral genes. Here we review the current knowledge of virus-induced signal transduction by seven human pathogenic viruses and the most widely used experimental models for viral infections. The molecular mechanisms of virus-induced expression of cytokines and chemokines is also analyzed.
INTRODUCTION
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A hallmark of a viral infection is an acute reaction by the infected cell. This includes activation of a preexisting antiviral defense machinery, commitment to apoptosis, and production of specific cytokines. These events contribute to the reduction of viral replication and to the limitation of viral spread. By focusing on some important human pathogenic viruses as well as widely used laboratory models for viral infections, this text will review the current knowledge of which viral components are responsible for inducing cytokine production and the mechanisms through which this occurs. The virus-induced cellular signal transduction pathways leading to the host response will also be discussed.
VIRUS-INDUCED SIGNAL TRANSDUCTION AND CYTOKINE EXPRESSION
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Immediately following a viral infection, a strong host response is
initiated. For a range of viruses it has now been clarified that the
mere interaction of viral surface proteins with cellular surface
proteins starts a cellular reaction that in many cases leads to the
first wave of cytokine production after infection (Table
1 and Fig.
1). In addition, many viral proteins not
present in the infectious particle but produced during the course of
the viral life cycle are able to affect cellular signaling in a manner leading to cytokine production. Moreover, accumulation of viral RNA and
overload of the cellular protein synthesis machinery induces signals
that are able to trigger an early host response to the infection. The
importance of such alert signals in the clearance of viral infections
is illustrated by the fact that many viruses have adopted mechanisms to
interfere with these processes (32, 33, 160, 197, 201).
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With respect to cytokine induction, some of the most important signal
transduction pathways activated by viruses are shown in Fig.
2. Interferon (IFN) regulatory factor 3 (IRF-3) and IRF-7 are recently discovered virus-activated transcription
factors that have been ascribed an important role in IFN-
/
expression (155). These transcription factors become
activated by serine/threonine phosphorylation (see below). The
mitogen-activated protein (MAP) kinases p38 and Jun N-terminal kinase
(JNK) are also activated in response to many viruses. Following
activation, the serine/threonine kinases phosphorylate their downstream
targets, notably activating transcription factor 2 (ATF-2) and Jun,
thus promoting their trans-activating potential (reference
97 and references therein). Jun can form homodimers as
well as heterodimers with ATF-2 and Fos. The ATF-2/Jun dimer binds to
the cyclic AMP response element (CRE), whereas the Jun homodimer and
the Jun/Fos heterodimer recognize the TPA-responsive element
(253). Another transcription factor activated in response to virus infection is nuclear factor of activated T cells (NF-AT). NF-AT is constitutively present in the cytoplasm in a latent
phosphorylated form. Increasing levels of cytoplasmic calcium activate
the calmodulin-dependent phosphatase calcineurin, which activates NF-AT
by dephosphorylation (56).
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Activation of NF-B is a hallmark of most infections including viral
infections (reviewed in references 91 and 228). This transcription factor is normally found in the cytoplasm complexed with
an inhibitory protein, IB, of which various isoforms exist. Upon
infection, signaling events are initiated leading to activation of MAP
kinase kinase kinases (MAP3K), which promote the activation of a large
kinase complex able to phosphorylate IB at two specific amino-terminal serine residues. The kinases responsible for IB phosphorylation are IB kinase (IKK ) and IKK .
Phosphorylated IB is subsequently targeted for degradation through
the ubiquitin-dependent 26S proteasome pathway. Degradation of IB
unmasks the nuclear localization signal of NF-B, which then migrates
to the nucleus and activates transcription. Table
2 summarizes how the viruses discussed in
this review affect the activity of cellular transcription factors.
NF-B activation by viruses has been the subject of particularly intense investigation, and it appears that a number of different mechanisms are employed (Fig. 3). As will
be described below, NF-B plays a central role in virus-dependent
cytokine expression and pathology.
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Herpes Simplex Virus
Herpes simplex virus (HSV) is a herpesvirus belonging to the
subgroup Alphaherpesvirinae. This group is characterized by
a rapid life cycle and spread, destruction of infected cells, and the
ability to establish latency in sensory neurons. HSV causes a number of
human diseases including cold sores, eye and genital infections, and
encephalitis. Primary HSV infections are generally more severe than
secondary infections, which tend to be more localized. On primary HSV
infection, the host responds by production of a range of cytokines.
These include interleukin-1 (IL-1), IL-2, IL-6, IL-10, IL-12,
IL-13, tumor necrosis factor alpha (TNF-), IFN-/, IFN-
, and
granulocyte-macrophage colony-stimulating factor (GM-CSF) (69,
81, 87, 94, 187, 246). In addition, the chemokines IL-8,
macrophage inflammatory protein 1 (MIP-1) and MIP-1, monocyte
chemoattractant protein 1 (MCP-1), and RANTES are produced during a HSV
infection (207, 236).
The HSV genome encodes at least 11 glycoproteins, which alone or in
concert play different roles in viral adsorption, entry, cell-to-cell
spread, immune evasion etc. (200). Glycoprotein D (gD)
is central to viral entry, which is dependent on the interaction of gD
with a cellular entry mediator. At present, three entry mediators have
been identified, termed HveA, HveB, and HveC (49, 168),
and of these at least the TNF receptor family member HveA is known to
be a signaling receptor (156). This fact suggests that gD
is an attractive candidate to play a role in the induction of the first
wave of cytokines, which are insensitive to UV treatment of the virus
and include IFN-/ and TNF-. Indeed, gD is responsible for
induction of IFN-. Ankel et al. showed that recombinant gD promotes
IFN- secretion whereas 7 other HSV glycoproteins do not
(8). Likewise treatment of murine macrophages with
recombinant gD triggers expression of TNF- (S. R. Paludan,
unpublished data). In addition to the rapid gD-dependent cytokine
induction, HSV infection leads to the production of other cytokines
through a different mechanism with slower kinetics. This mechanism is
UV sensitive and involves the cytokines IL-6 (116;
Paludan, unpublished) and IL-12 (154). The viral
components responsible for this second wave of cytokine induction have
not been unveiled.
Based on the above, HSV infection seems to trigger at least two
cellular signaling pathways: one UV insensitive and dependent on gD,
and one UV sensitive and dependent on a functional viral genome. The
early gD-dependent signaling is not well described, but HSV-2 infection
of murine macrophages induces enhanced DNA-binding activity of NF-B
and ATF-2/c-Jun within one hour post infection (Paludan, unpublished).
Although it has not been demonstrated how gD induces signaling, it is
interesting that HSV uses HveA as receptor and that HveA signaling
leads to activation of NF-B and activator protein 1 (AP-1)
(156). Since the HveA-induced signaling pattern is
compatible with the above-described observations in HSV-2-infected
macrophages, it is tempting to speculate that the early gD-dependent
cellular response proceeds through HveA. In fact, it has been reported
that HSV-1 infection of the human cervical carcinoma cell line C33
induces a weak and transient activation of NF-B and that this can be
abrogated with antibodies against gB and gD (189).
At later stages of infection (i.e., 3 to 4 h postinfection),
UV-sensitive signaling is initiated, leading to a strong activation of
NF-B and AP-1. The slower kinetics and UV-sensitive nature of the
AP-1 activation are explained by the finding that viral protein 16 (VP16)-dependent transcription precedes the activation of AP-1
(159, 269) and that it depends on the immediate-early protein infected-cell polypeptide 0 (ICP0) (113, 269). The
upstream kinases responsible for AP-1 activation by HSV are JNK and p38 (269). Likewise, the mechanism of sustained NF-B
activation by HSV is dependent on viral entry and immediate-early gene
expression. Specifically, Patel et al. showed that viruses with defects
in ICP4 and ICP27 were unable to induce persistent NF-B activation (189). In the same study it was demonstrated that
activation of NF-B promoted viral replication as evidenced by
prevention of replication by overexpression of a nondegradable form of
IB, thus preventing NF-B activation. A possible target for
NF-B in the viral genome is the ICP0 promoter, to which NF-B has
been reported to bind (206). Interestingly, activation of
NF-B in macrophages by HSV-2 infection is responsible for the
enhanced expression of nitric oxide synthase type 2 following virus
infection (186, 188), and it is well documented that
nitric oxide is a potent antiviral product (57, 118). This
demonstrates the double-edged-sword-like nature of NF-B activation
by HSV and other viruses, since the transcription factor is involved in
both viral replication and the protective host response to the infection.
In addition to the effect of HSV infection on cellular signaling pathways, viral proteins with trans-activating potential may directly affect transcription. For instance, VP16 interacts with the host proteins octamer transcription factor 1 (Oct-1) and host cell factor (131) to induce the transcription of the immediate-early viral genes and potentially some host genes. Moreover, ICP0 cooperates with the human immunodeficiency virus (HIV) protein Tat to activate the HIV long terminal repeat (LTR) (219), and it seems very likely that ICP0 or other HSV immediate-early proteins may also modulate the function of cellular transcription factors, although this has not yet been reported.
There is some evidence about the molecular mechanisms through which
HSV-induced cytokine production occurs. Fitzgerald-Bocarsly and
associates reported that production of IFN- was inhibited by the
calcium chelator EGTA and was sensitive to inhibitors of protein kinase
C (PKC) and tyrosine kinases, whereas inhibitors of the cyclic
AMP-dependent protein kinase PKA had no effect (143). We
have shown that expression of TNF- by HSV-2-infected murine macrophages relies on NF-B and a p38-dependent pathway, possibly ATF-2/Jun (Paludan, unpublished). Treatment of the macrophages with
either pyrrolidine dithiocarbamate or SB203580, which inhibit the
activation of NF-B and p38, respectively, prevented HSV-2-induced TNF- expression. This demonstrates a requirement for both signals in
order for HSV-2 infection to bring about TNF- expression. Finally,
there is evidence that the ability of HSV-2 to trigger the expression
of the IL-12 subunit p40 is dependent on NF-B activation
(154).
In concert, the cellular response to an HSV infection seems to be biphasic, with an early response which is dependent on viral surface and tegument proteins and a later response involving factors produced during the viral replication cycle. With the growing focus on virus-induced cellular signaling and transcriptional regulation, this field is rapidly accumulating the information required to better explain HSV-induced cytokine expression at the molecular level, which will be an important step in our understanding of the pathology of HSV infections.
Cytomegalovirus
Cytomegalovirus (CMV) is a herpesvirus belonging to the
Betaherpesvirinae subgroup. CMV infects most cell types and
establishes latency in leukocytes. A CMV infection is normally
subclinical but can be fatal in immunocompromised individuals or if the
infection is acquired in utero. The cytokine profile of the early phase of CMV infection is typically proinflammatory, with production of
IL-1, IL-6, IL-12, TNF-, IFN-/, and IFN- (38, 183, 192, 235, 266). One of the major components of the CMV virion is
the glycoprotein gB, and studies have shown that a significant proportion of the virus-host interactions are mediated through gB
(27, 267). For instance, induction of IL-1 in monocytes can be blocked by anti-gB (266). Likewise, in studies on
the mechanism of IL-6 induction by human CMV, it was shown that
UV-inactivated virus retained the ability to induce IL-6 production,
which was independent of immediate early virus transcription and could
be inhibited by neutralizing antibodies against gB (38).
As will be described below, CMV stimulates a large number of typical
proinflammatory signaling events, including nuclear translocation of
NF-B (267), and many of these can be mimicked by
recombinant gB. Although gB is able to interact with heparan sulfate
proteoglycans, which are essential for viral entry (53),
these do not appear to be involved in the gB-dependent signaling. The
biphasic nature of the Scatchard plot for the cell-gB interaction
supports the notion that in addition to heparan sulfate proteoglycans,
the viral glycoprotein has a second, as yet unidentified receptor which
may be responsible for the signaling (26).
As to the CMV-stimulated cellular signaling, it has long been known
that one of the early cellular responses to human CMV infection is
production of inositol 1,4,5-triphosphate and 1,2-diacylglycerol (241). The subsequent calcium flow and PKC activation have
been suggested to be involved in early activation of transcription factors interacting with DNA motifs, including B, CRE, and
TPA-responsive element (23). In addition, the human CMV
particle has been demonstrated to carry phosphatase activity
(163) and to activate the membrane-proximal phospholipases
C and A2 as well as the MAP kinases extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) and p38 immediately following infection (2, 27, 241). The mechanism of
activation of NF-B by CMV has been studied in some detail, and it
was shown that the early NF-B activation can be ascribed to
liberation of the transcription factor from the inhibitory subunit
IB but not IB (266). Moreover, NF-B
activation is mediated by a gB-dependent mechanism. Interestingly, the
early activation of NF-B is amplified by other mechanisms later
during infection. This second wave of NF-B activation relies on an
NF-B-dependent activation of the CMV major immediate-early promoter.
Cooperation of IE1-72, IE2-55, and IE2-86 proteins with the cellular
transcription factor selective promoter factor 1 (Sp1) up-regulates the
promoters for the NF-B subunits p65 and p105/p50 (211,
268).
Contrasting results have been obtained with regard to activation of CRE-binding activity by CMV. The rapid activation reported for human CMV infection (23) was not seen in murine CMV-infected macrophages (266). Another study showed that ATF/CRE-binding protein (CREB) DNA-binding activity was indeed induced following human CMV infection, but only at late time points after infection (121). These observed discrepancies are probably due to the use of different cell types as well as differences in the way the cells were treated. While some investigators serum-starved cells prior to stimulation, others did not. Moreover, it cannot be excluded that the differences between human and murine CMV may give rise to some nonreconcilable results. Human CMV has also been reported to activate IRF-3 (180), through a rapid de novo protein synthesis-independent mechanism.
The role of CMV-activated signaling in cytokine induction has been
clarified to only a limited extent. NF-B appears to be involved in
the expression of both IL-1 and IL-6 (38, 266). In
addition, p38 and G proteins are involved in induction of IL-1 and
IL-6 production, respectively. Taken together, CMV infection triggers a
proinflammatory host response induced at least partly via the
interaction of gB with a cellular receptor. A great deal is now known
about the signaling events and pattern of transcription factors
activated following CMV infection. One of the main challenges is to
identify the cellular CMV receptor and to explain molecularly how
virus-activated cellular signaling brings about the observed cytokine profile.
Epstein-Barr Virus
The Gammaherpesvirinae family member Epstein-Barr virus
(EBV) is a lymphotropic herpesvirus with oncogenic potential. During a
primary EBV infection, the virus undergoes lytic replication in
epithelial cells and B lymphocytes, where it establishes latency. EBV
is the causative agent of infectious mononucleosis and is involved in
the development of a variety of human malignancies including
Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma
(reviewed in references 17 and 107). The acute host response to an EBV infection is normally vigorous, with high fever, swollen glands, and splenomegaly. The first wave of cytokines and
chemokines produced during EBV infection includes IL-1, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-8, IL-18, TNF-, IFN-/, IFN-, monokine induced by IFN- (Mig), IFN--inducible protein 10 (IP-10) and GM-CSF (61, 139, 150, 158, 204, 205, 226, 233).
As is the case for the above-described herpesviruses, EBV surface
proteins are also able to trigger many of the early characteristics of
the infection. For example, treatment of human monocytes/macrophages with recombinant EBV glycoprotein gp350 leads to the production of
IL-1 and TNF- (60, 61). Moreover, UV-treated virus
can induce production of IL-1Ra, IL-6, IL-8, MIP-1, and GM-CSF in a
variety of cell types, and this effect is neutralized by antibodies against gp350 (158, 204, 205, 233). In addition to gp350, the EBV protein latent membrane protein 1 (LMP-1) is able to trigger the production of some cytokines such as IL-6, IL-8, and IL-10 (68, 175). As described below, LMP-1 gives rise to a
strong signaling response, and this suggests that involvement of this protein in the induction of still more cytokines is likely to be
revealed as studies progress. Finally, there is evidence that the EBV
nuclear antigen 2 (EBNA2), a DNA-binding protein required for
B-lymphocyte immortalization, induces IFN-/ expression in Burkitt's lymphoma cell lines (117).
Parts of the intracellular signaling induced by EBV have similarities
to those of HSV and CMV, while others are unique to EBV. The mechanism
of action of gp350 is through the cellular receptor complement receptor
2 (CD21), which is known to be a signaling receptor (25,
230). This receptor engagement induces specific tyrosine
phosphorylation (24) as well as activation of PKC,
phosphatidylinositol 3-kinase (PI-3K), and NF-B (61, 230). The pathway leading to NF-B activation seems to include IKK, since it was shown to be sensitive to sodium salicylate
(230), which at low millimolar concentrations inhibits IKK
(263). Two EBV immediate-early proteins, BZLF-1 and
BRLF-1, also activate cellular stress pathways (1). They
function as transcriptional activators of EBV early genes and are
sufficient for reactivation of latent EBV infections. The two
immediate-early proteins activate p38 and JNK and the downstream
transcription factors ATF-2 and c-Jun (1). This process is
essential for the ability of BZLF-1 and BRLF-1 to promote EBV
reactivation. EBNA2 represents yet another EBV-encoded protein with the
capacity to modulate cellular signaling. In one study it has been shown
that EBNA2 trans activates the HIV-1 LTR and that this
function can be ascribed to activation of NF-B (218).
The mechanism of NF-B activation by EBV represents a
particularly well-documented example of biphasic kinetics of NF-B
activation, as observed for some viruses. First the mere interaction of
gp350 with its cognate cellular receptor CD21 induces intracellular signaling from CD21, resulting in rapid activation of NF-B
(61, 230). At later stages of infection, LMP-1 is produced
and inserted in the cellular membrane. The cytoplasmic portion of LMP-1
has similarities to the TNF receptor and recruits many of the same adapter proteins and kinases (173). Consequently, like the
TNF- receptor, LMP-1 activates NF-B through a mechanism common to many stimuli (111, 231), where upstream signals converge
at the NF-B-inducing kinase (NIK) followed by activation of IKK and
subsequent nuclear translocation of NF-B. In line with the similarity to the TNF receptor, LMP-1 also activates AP-1
(82). This activation process occurs through a pathway
involving stress-enhancing kinase and JNK (82). Moreover,
LMP-1 also activates p38 and the downstream transcription factor ATF-2
(68). Finally, there is now evidence that LMP-1 induces
expression of the recently identified IRF-7 (272). Given
the reported functions of IRF-7, the discovery that LMP-1 induces IRF-7
expression will probably unveil yet more roles of this viral protein in
cell signaling in infected cells.
Among the signaling pathways activated by EBV, some have been
specifically demonstrated to be involved in the induction of cytokine
production. The ability of gp350 to induce the secretion of IL-6 in B
lymphocytes can be abrogated by specific inhibitors of PKC, p38 and
tyrosine kinases, implying a role of these factors in the signaling
from CD21 to the IL-6 promoter (68, 233). The MAP kinase
p38 is also involved in gp350-dependent IL-8 production (68). Finally, there is evidence that the expression of
IL-1 and TNF- by human monocytes/macrophages after exposure to
gp350 is dependent on PKC, PI-3K, and NF-B (60, 61). Of
the LMP-1-induced cytokines, production of IL-6 and IL-8 has been found
to be dependent on the p38 pathway (68). For IL-8, it was
further shown that the AP-1- and NF-B-binding motifs confer the
majority of the LMP-1 responsiveness whereas the CCAAT enhancer-binding
protein (C/EBP) motif did not seem to be involved. Participation of
other specific signaling pathways in LMP-1-induced cytokine production has not been reported but seems possible, given the extensive signaling
from this membrane protein.
Taken together, it seems that gp350 is responsible for the majority of
the initial host response to EBV infection whereas later signaling
events in the infected cell are heavily influenced by LMP-1. The fact
that EBV is endowed with strong NF-B activation properties may not
seem beneficial for the virus, given the pivotal role of this
transcription factor in host defense. NF-B is, however, also
involved in antiapoptotic regulation in the cell and is important for
cell transformation by EBV (35).
Influenza Virus
Influenza virus, which is the causative agent of influenza, is an
orthomyxovirus that can establish infection in the epithelium of the
upper and lower respiratory tract after entry through the oral or nasal
route. The virus, which has a negative-sense segmented RNA genome,
possesses an outer lipid membrane containing the two proteins
hemagglutinin (HA) and neuraminidase (NA). HA is responsible for viral
cell attachment through interactions with sialic acids on the cell
surface, and NA cleaves sialic acids and promotes viral release
(221). A typical influenza virus infection results in
fever, myalgia, and cough. The symptoms start between 1 and 4 days
postinfection and persist for 3 to 5 days. In immunocompromised individuals, influenza virus infection can result in a more severe clinical outcome and may even be fatal. The disease symptoms are due
both to immunopathology and cytopathic effects of the virus (18). A whole range of cytokines and chemokines are
induced during an influenza virus infection in different cell types.
These include IL-1, IL-2, IL-6, IL-8, IL-10, IL-15, IL-18, transforming growth factor (TGF-), TNF-, IFN-/, IFN-, GM-CSF,
MIP-1/, and RANTES (71, 93, 96, 101, 114, 128, 167, 194,
212, 213, 223).
In early studies on the mechanism of induction of cytokines by
influenza virus, it was noted that different influenza A virus strains
differ in their ability to induce IFN-/ (44). It was further shown that the IFN-inducing potential of a specific strain correlated with the NA activity. Houde and Arora showed that
recombinant NA, but not HA, induced the production of IL-1 and TNF-
in murine peritoneal macrophages (9, 104, 105), and
another study has shown that NA promotes the conversion of TGF- from
the latent to the active form to an extent sufficient to induce
TGF--dependent apoptosis (223). The exact mechanism
through which NA induces cytokine expression remains obscure yet is
very important, given the high immunostimulatory activity of this viral protein.
The cellular signaling induced by influenza virus infection results in
activation of the MAP kinases p38 and JNK and the downstream transcription factors NF-B, AP-1, and CRE-binding factors (34, 101, 128). It has as yet not been shown which upstream signaling pathways are responsible for this response, nor has it been shown if
and how the viral envelope proteins initiate the response. It will be
interesting to learn if the cytokine-inducing potential of NA is
dependent on interaction with a cellular receptor or on the enzymatic
activity of NA. The latter is not impossible, since gangliosides
(sialic acid-containing glycosphingolipids) have been reported to
activate the MAP kinases ERK, JNK, and p38, as well as the
transcription factor NF-B, in rat microglia (198). As
to the cellular response following exposure to HA, several studies have
shown that overexpression of HA induces activation of NF-B
(16, 72, 184). The mechanism of NF-B activation has
been suggested to include overload of HA in the endoplasmic reticulum
(ER), a process which is known to activate NF-B through the release
of calcium (185). Two other influenza virus proteins, matrix protein and nucleoprotein, have also been reported to promote NF-B activation, although this occurs through an ER-independent mechanism. For all three NF-B-activating viral proteins, IKK is
part of the activation pathway (72).
In addition to viral proteins, influenza virus double-stranded RNA
(dsRNA) is sensed by the infected cell as an alert signal (90). As will be described below in more detail, dsRNA
initiates signaling events through a mechanism dependent on the
dsRNA-activated protein kinase (PKR). This PKR-dependent virus-induced
cellular stress response is an important part of the first line of
defense against virus infections (for reviews, see references 254
and 255). The influenza virus has, however, developed mechanisms to mask the potent PKR-activating ability of its RNA. In fact, influenza virus inhibits the action of PKR by two mechanisms, one
involving up-regulation of the cellular PKR inhibitor p58 (160) and one involving the viral nonstructural protein 1 (NS1) (90). Given the well-described role of PKR in
virus-induced signal transduction and IFN-/ expression
(130, 259), it is no surprise that NS1 counteracts the
activation of NF-B and induction of IFN-/ by influenza A virus
(249). Despite these mechanisms to down-modulate PKR
activity, there is evidence that influenza virus activates the kinase
to some extent and that the subsequent cellular signaling triggers
apoptosis (232).
Molecular understanding of cytokine and chemokine induction by
influenza virus has so far not reached a level comparable to that for
some of the other viruses discussed in this review. It is known that
influenza virus-induced IL-8 relies on activation of NF-B
(127) and that the ability of influenza virus to regulate the expression of RANTES involves p38 and JNK (128). Given
the NF-B-activating capacity of HA, there is reason to believe that HA induces the production of certain cytokines. Investigation of the
molecular mechanisms that govern influenza virus-induced cytokine
expression constitutes an important task for this research field and
may provide new information about the molecular events that form the
basis for the pathogenesis of influenza virus infection.
Hepatitis B Virus
Hepatitis B virus (HBV) is an enveloped DNA virus belonging to the family of hepadnaviruses. HBV has a strict tissue tropism to the liver, causing acute or chronic hepatitis, and is furthermore associated with the development of cirrhosis and hepatocellular carcinoma. Initially, the virus replicates in hepatocytes with few or no cytopathic effects, correlating with the lack of liver damage. The HBV genome is integrated into host DNA, and the infection may remain latent. At later stages, accumulation of filamentous HBV surface antigen (HBsAg) gives rise to the ground-glass hepatocyte pathology characteristic of HBV infection. As is the case in many virus infections, cell-mediated immunity and inflammation, rather than cytopathic effects caused by viral replication, are the main mediators of the hepatic pathology induced by HBV infection (42).
Given that the hepatic damage observed during acute or chronic
hepatitis appears to be caused mainly by the intrahepatic inflammatory processes evoked by the immune response to HBV, much effort has been
made to determine the cytokine profile of HBV infections as well as the
cellular sources of the cytokines produced. Numerous reports have shown
that HBV infection is associated with the production of a broad range
of proinflammatory cytokines and chemokines such as IL-1, IL-6,
IL-8, IL-12, TNF-, and IFN- (3, 80, 83, 106, 153,
182), as well as the anti-inflammatory cytokine IL-10 (106, 242). While some investigators have shown that
proinflammatory cytokine production may be required for viral clearance
(80, 208), others report that excessive synthesis of IL-6
may eventually lead to liver cirrhosis and hepatocellular carcinoma
(142). Yet other laboratories have demonstrated a
predominant Th1 cytokine profile in acute self-limiting HBV infection
(191). However, it has been difficult to demonstrate any
direct correlation between the type of cytokines produced and the
outcome of infection, since a fine balance between viral clearance and
extensive hepatocyte necrosis seems to exist. With regard to the cell
type responsible for cytokine production, IFN- has been shown to be
produced predominantly by Th1 cells (106) whereas others
have demonstrated TNF- and IL-6 production by hepatocytes (83,
142).
As to which viral components are responsible for cytokine induction, a
number of studies have addressed this question. One of the best-studied
proteins is the HBV x protein (HBx), which functions as a
transcriptional activator, although it does not bind directly to DNA
(95). Instead, HBx plays the role of a dual-specificity
activator of transcription, stimulating signal transduction pathways in
the cytoplasm as well as acting directly on transcription factors in
the nucleus (95). HBx is essential for viral infection and
up-regulates a range of cellular and viral genes, even though its
precise role in the viral replication cycle is still unknown. Growing
evidence links HBx to hepatocarcinogenesis (6), but the
exact mechanism initiating intrahepatic inflammatory events remains
elusive. However, HBx induces several cytokines and chemokines,
including IL-6, IL-8, and TNF- (138, 142, 153), findings that may at least partly explain the role of HBx in hepatic pathology.
In addition to HBx, the surface antigen (HBsAg) and core antigens
(HBcAg and HBeAg) stimulate cytokine production. HBsAg was reported to
trigger the production of IL-2, IL-10 and IFN- (106, 140) while HBcAg and HBeAg promote the secretion of IL-10,
TNF-, and IFN- (106, 242). Since the specific nature
of the HBV receptor and the mechanism of HBV entry remain unresolved,
it is not certain if the cytokine-inducing capacity of these viral
proteins is dependent on interaction with specific cellular receptors
or is a secondary effect triggered by lymphocyte activation. Results
from one study indicate that HBsAg does have properties as a
transcriptional activator (see below), suggesting that at least part of
the cytokine-stimulating function of this major HBV surface protein is
due to a direct effect on signal transduction (98).
Most of the work addressing the signal transduction stimulated by HBV
has been performed as overexpression studies in cell lines, while
results with infectious virus are lacking behind. This is at least
partly due to the lack of a cell culture system to grow HBV.
Nevertheless, significant advances have been made in recent years. A
series of elegant studies conducted in the laboratory of R. J. Schneider have contributed significantly to our knowledge of
HBx-stimulated signaling. The emerging picture is that HBx affects the
majority of the proinflammatory signaling cascades in a stimulatory
fashion. For instance, HBx activates the MAP kinase network through
MEKK1, the GTPase Ras, and the serine/threonine kinase Raf
(19, 20). This leads to downstream activation of JNK
and ERKs, respectively, eventually stimulating transcription factors,
most notably AP-1, ATF-2, and NF-B. As in the case of AP-1, NF-B
activation by HBx has been demonstrated to involve Ras activation
(19, 58, 178, 229). HBx appears to activate NF-B
through two distinct cytoplasmic pathways, namely, by inducing
phosphorylation and subsequent degradation of IB and by reducing
the cytoplasmic levels of p105, the inhibitory precursor of p50
(229). Other transcription factors affected by HBx include
AP-2, C/EBP, early growth response factor 1 (Egr-1), and NF-AT
(43, 119, 137, 138, 153, 265). However, the exact nature
of the signals is still partly unknown, since some data indicate that
they are independent of calcium and PKC (19) while other
data suggest that PKC may be involved (119).
HBx interacts with cellular functions through a dual mechanism, being
able to act both in the cytoplasm by activating signal transduction
cascades as described above and in the nucleus by interfering with the
basal transcriptional machinery (6). The latter mechanism
involves interaction between HBx and transcription factor IIB (TFIIB),
TFIIIB, RNA polymerase II (92, 147), and increased levels
of TATA-binding protein (247), as well as association with
transcription factors such as CREB/ATF (152) and C/EBP (43). Of particular interest is the interaction between
HBx and C/EBP, which synergistically activates the HBV enhancer
II/pregenomic promoter, thereby promoting viral replication
(43). The ability of HBx to enhance C/EBP activity also
affects IL-8 expression (153). In fact, it was shown that
HBx-induced IL-8 production was dependent on cis elements
for C/EBP and NF-B. Another study has shown that TGF-1 expression
is elevated in HBx transgenic mice (265). Moreover, the
authors demonstrated that association of HBx with the Egr-1 protein
promotes TGF-1 expression. Finally, the molecular mechanism of
HBx-induced TNF- expression in the hepatocyte-derived cell line
HepG2 has been investigated (138). In parallel with what
has previously been observed for a number of other TNF- stimulators,
HBx was found to augment TNF- expression through a mechanism
involving NF-AT and AP-1.
As described above, there is evidence that HBsAg is able to activate
transcription. Hildt et al. (98) found that the protein resulting from the large translational product of the HBsAg gene (LHB)
activates AP-1 and NF-B. The HBsAg gene can be translated from three
in-frame start codons, with LHB containing the pre-S1, pre-S2, and S
regions. The middle product (MHB) encompasses the pre-S2 and S regions,
while the small product (SHB) contains the S region only. The
activating function of HBsAg is dependent on cytoplasmic orientation of
the pre-S2 region, as is the case for newly synthesized LHB and a
carboxy-terminal truncated version of MHB, termed MHBst. For
full-length MHB, however, the pre-S2 region is oriented toward the
lumen of the ER, thus preventing it from activating cellular signaling.
The pre-S2-induced events rely on direct interaction with PKC, and it
was shown that downstream activation of the kinase c-Raf-1 is a
prerequisite for LHB-dependent activation of AP-1 and NF-B. LHB thus
provides an elegant example of how viruses with small genomes have
evolved mechanisms to compensate for this apparent drawback by endowing
the proteins with multiple functions. LHB is expressed on the surface
of the HBV virion, is essential for assembly of the virus particle, and
also seems to support the activation of the viral promoters.
In summary, virus-host interactions during an HBV infection are attributed mainly to HBx, although HBsAg, HBcAg and HBeAg also contribute. The resulting immune response is known to play a significant role in the pathology of HBV-mediated hepatitis. With the growing information available on the molecular events underlying HBV replication and HBV-induced cellular signaling, the frontiers in this area of research include exploitation of our knowledge to design new strategies for treatment in the clinic.
Human Immunodeficiency Virus
HIV is a retrovirus of the Lentivirus subfamily. It
infects CD4 T lymphocytes and monocytes/macrophages through recognition of the CD4 receptor and the coreceptors CXCR4 and CCR5 (181, 243). Following an acute viremia, resulting in a mononucleosis- or influenza-like condition, a state of clinical latency is reached in
which CD4 T lymphocyte turnover is vastly increased. However, eventually the immune system (the T lymphocytes in particular) becomes
unable to keep pace with the extensive turnover and death of cells,
leaving a state of immunoincompetence and AIDS. Although macrophages
are not killed by HIV infection, they display dysfunction and serve as
a reservoir and source of HIV in the organism. The acute host response
to a primary HIV infection is characterized by a Th0 cytokine profile
including the proinflammatory cytokines IL-1, IL-2, IL-6, TNF-,
IFN-/, and IFN- (86, 202, 238), as well as the
anti-inflammatory cytokines IL-4, IL-10, and IL-13 (86,
190). At later stages of infection, as full-blown AIDS progresses, the pattern of cytokine production shifts toward a strongly
biased Th2-like response (47, 48, 115). The mechanisms of
HIV-induced cytokine production have been studied in great detail, and
much information is available about the early cytokine expression
whereas less is known about what causes the shift in cytokine profile.
The HIV glycoprotein gp120, which interacts with CD4 and the chemokine
receptors CXCR4 and CCR5, is able to induce the secretion of many
proinflammatory cytokines including IL-1, IL-1, IL-6, IL-8,
TNF-, IFN-/ and IFN- (5, 7, 36, 73).
Interestingly, gp120 is also able to induce the secretion of IL-4 and
IL-13 in basophils (190) and IL-10 in mononuclear cells
(220), indicating that the acute Th0-like host response to
HIV is explained largely by the interaction of gp120 with cellular
receptors. While most gp120-induced functions are explained by its
interaction with CD4, the mechanism through which IL-4 and IL-13 are
induced appears somewhat different. Recombinant gp120 from various
divergent HIV-1 isolates was found to induce secretion of IL-4 and
IL-13 in basophils, and this occurred by the action of gp120 as
superantigen (190), where gp120 binds to the
VH3 region of immunoglobulin E and hence enhances the
action of immunoglobulin E on Fc
RI.
Another HIV protein, Tat, is known to stimulate the production of many
cytokines. Tat is produced by HIV-infected cells and has pleiotropic
effects on viral replication and cell growth (for a recent review, see
reference 74). Tat is predominantly cytoplasmic but can be
released from infected cells and enter adjacent cells. The protein
contains an arginine-rich domain that permits Tat to efficiently cross
membranes (224). The cytokines and chemokines induced by
Tat include IL-1, IL-2 IL-6, IL-8, TGF-1, TNF-, and MCP-1
(39, 100, 145, 177, 216, 252). A third HIV protein able to
induce cytokine production is Nef. This regulatory protein is produced
early in the HIV life cycle and is important for viral infectivity and
pathogenicity (59). As with Tat, Nef is predominantly cytoplasmic, but soluble Nef as well as anti-Nef antibody can be
detected in sera from HIV patients (76). Although
cytoplasmic Nef is immunomodulatory (see below), it is not as potent an
inducer of cytokine production as is extracellular Nef, which induces the production of IL-1, IL-6, IL-10, IL-15, TNF-, and IFN- in
various human leukocyte populations (29, 63, 199). Finally there is evidence that viral protein R (Vpr) induces the expression of
IL-6, IL-8, IL-10, TNF-, and IFN- in a variety of cell types (209). Vpr, which is required for optimal replication of
HIV in vivo, is produced late in the HIV life cycle and assembled into
the virion (50). Vpr has, furthermore, been suggested to be important for replication of HIV in macrophages (15).
HIV infection affects cellular signaling activity in a very profound
manner. At present, signaling properties have been reported for all HIV
proteins discussed in this review. gp120 induces signaling mainly
through interaction with CD4, but there is also evidence that the
chemokine receptors CXCR4 and CCR5 signal following interaction with
gp120. The CD4-dependent signaling has been elucidated mainly through
studies performed in the laboratory of P. M. Pitha. Binding of
gp120 to CD4 results in activation of the tyrosine kinase Lck and the
serine/threonine kinase Raf-1 (196). This receptor
engagement also induces activation of the MAP kinases ERK1, ERK2, and
JNK, as well as the transcription factors NF-B, AP-1, and C/EBP
(NF-IL6) (135, 195). Two studies have shown that gp120
triggers signaling from the coreceptors CXCR4 and CCR5, as evidenced by
phosphorylation of the protein tyrosine kinase Pyk2 (62,
166). Interestingly, however, whereas the natural CXCR4 ligand
stromal cell-derived factor 1 also activates MAP kinase pathways,
this was not seen in response to gp120, indicating that gp120-induced
chemokine receptor signaling does not fully mimic the response to chemokines.
The Tat protein activates cellular signaling cascades and transcription
factors associated with a proinflammatory host response, and, indeed,
Tat is a potent inducer of many proinflammatory cytokines. However,
given that the HIV LTR is regulated by transcription factors of the
NF-B, NF-AT, Sp1, and C/EBP families (89, 125, 174, 210,
244), this property of Tat is beneficial for viral replication.
Activation of NF-B by Tat proceeds via IKK, which is constitutively
active in HIV-infected cells (64). Moreover, the ability
of Tat to activate NF-B also seems to require PKR (66).
Interestingly, the involvement of PKR in NF-B activation is not
restricted to Tat, since PKR-deficient cells also display an impaired
ability to activate NF-B in response to TNF- and dsRNA
(270). The specific nature of the upstream kinases
regulating IKK activity has not yet been reported. In addition to the
IKK pathway, some earlier studies showed that activation of PKC by Tat
leads to nuclear translocation of NF-B (54). At present it is not known if the PKC-dependent pathway represents an alternative mechanism of NF-B activation by Tat or if Tat activates NF-B by
one sole mechanism involving PKC, PKR, and IKK.
It has been shown that Tat primarily targets IB for degradation
(65). Tat expression leads to constitutive activation of
NF-B, which is normally associated with degradation of IB rather than of IB (237). IB degradation and
synthesis are subject to autoregulation due to the presence of
NF-B-responsive sites in the IB promoter (40).
Hence, IB-dependent activation of NF-B is normally
self-limiting. One study has addressed this apparent discrepancy and
showed that nuclear IB is at least partly responsible for the
observed constitutive NF-B activity in HIV-infected cells
(64). Nuclear hypophosphorylated IB is known to
maintain NF-B DNA binding by rendering the protein-DNA complex
insensitive to IB-mediated dissociation from DNA (10, 193), and DeLuca et al. showed that this mechanism contributes to the sustained NF-B activity in HIV-infected cells
(64). JNK, which is responsible for phosphorylation of
c-Jun and, to a lesser extent, ATF-2, is also regulated by Tat. It was
demonstrated that Tat activates JNK and AP-1 in the human histocytic
lymphoma cell line U937, whereas the effect on ATF-2/c-Jun activity was not examined (129). Similar findings have been achieved in
another study, where it was further shown that Tat activates the ERK
kinases (165).
Another transcription factor regulated by Tat is Sp1, which is
essential for optimal activation of the HIV LTR (89). Sp1 is a ubiquitous transcription factor involved in basal and inducible expression of many genes. Tat enhances Sp1 DNA binding and augments Sp1
phosphorylation, which was shown to be associated with enhanced promoter activity (46, 145). The kinase responsible for
phosphorylation of Sp1 in response to Tat remains unknown but may be a
DNA-dependent protein kinase, which has been shown to phosphorylate Sp1
on simian virus 40 infection (112). Sendai virus infection
has also been reported to augment Sp1 DNA binding to the TNF-
promoter in vivo (70). Of other transcription factors
affected by Tat, notably NF-AT and C/EBP have received attention,
due to their ability to regulate HIV LTR activity (125,
210). NF-AT activation by Tat is cyclosporin A sensitive
(252), implying a role of calcineurin in the process. In
addition, Tat is able to associate with NF-AT, thus enhancing
NF-AT-driven transcription (151). Similarly Tat-dependent DNA binding of C/EBP is at least partly attributed to complex formation between the two proteins, which enhances the DNA affinity of
C/EBP (4).
At present, very little is known about the signaling events induced by extracellular Nef, whereas more extensive knowledge has been gathered about the signaling induced by cytoplasmic Nef. However, given the limited cytokine-inducing function reported for cytoplasmic Nef, this will not be discussed in this review. Extracellular Nef may bind to a cellular receptor and initiate signaling or bind to cation channels leading to cation flow. It has been reported that Nef affects potassium and calcium channel activity in lymphocytes (271). Finally, it should be mentioned that despite the growing body of literature on extracellular Nef, the concept of extracellular Nef is not broadly accepted in the field.
The effects of Vpr on cellular signaling and gene transcription have
also been studied, and the data available suggest that Vpr modulates
the function of a number of DNA-binding proteins through direct
protein-protein interactions. It was first shown that the ability of
Vpr to stimulate HIV LTR transcription was mediated mainly through
physical interaction between Vpr and Sp1 bound to the HIV LTR
(248). Subsequent studies have shown that Vpr also
interacts with p53 and that this association antagonizes Vpr/Sp1-driven
transcription (215). The glucocorticoid receptor (GR) is
also a target for Vpr (124). The interaction between GR
and Vpr, which is dependent on the LXXLL motif of Vpr, facilitate the
recruitment of general transcription factors to GR. Thus, Vpr functions
as a transcriptional coactivator for GR-driven transcription. Finally,
a recent report has documented that Vpr enhances the trans-activating function of NF-B and C/EBP
(209).
The extensive knowledge about cytokine induction and signal
transduction by HIV gp120 is unfortunately not accompanied by a similar
in-depth understanding of which signaling pathways are responsible for
gp120-induced cytokine synthesis, although it was speculated in one
report that activation of AP-1 by gp120 may lead to the expression of
IL-3 and GM-CSF (41). For the mechanisms of Tat-induced
cytokine production, a substantial amount of knowledge has been
gathered. There is evidence that NF-B is pivotal for expression of
IL-2, IL-6, IL-8, TNF-, and MCP-1 (39, 120, 145, 252)
by Tat. The up-regulation of MCP-1 expression by Tat represents a
particularly well-documented study. Lim and Garzino-Demo provided
evidence that ectopic expression of Tat in the human astrocytoma cell
line U-89 triggered MCP-1 expression and that this phenomenon relied on
the synergistic action of Sp1, AP-1, and NF-B (145).
Other studies have shown that Tat-supported IL-2 expression relies on
the ability of Tat to activate NF-B and NF-AT, both of which are
required to activate the IL-2 promoter (240, 252).
Finally, there is evidence that Tat enhances the DNA-binding activity
of C/EBP and NF-B to the human IL-6 promoter, which promotes IL-6
expression (4, 120, 217). Together with the knowledge that
NF-B and C/EBP interact physically (210), these
results indicate that Tat stimulates IL-6 expression both by activating
specific transcription factors and by aiding the formation of stable
enhanceosome complexes.
For extracellular Nef, it is known that induction of IL-10 secretion is
sensitive to the calcium-calmodulin phosphodiesterase inhibitor W7 and
the calcium-chelating agent EGTA, suggesting that Nef-induced calcium
flux is involved in IL-10 induction (29). The ability of
Vpr to stimulate IL-8 expression is dependent on NF-B and C/EBP
(209). Moreover, a number of other cytokines controlled by
NF-B- and C/EBP-responsive promoters are induced by Vpr
(209), indicating that these two transcription factors play a central role in the induction of cytokines and chemokines by Vpr.
In addition to the induction of cytokines by the HIV proteins discussed
in the present section, there is accumulating evidence that these
proteins contribute to the shift in immune response toward a strongly
biased Th2-like response. For instance, Nef decreases the production of
IFN- and IL-2 (51) and has also been reported to impair
the signaling of Th1 cytokines (52). In addition to Nef,
Tat supports Th2-cell development by inducing expression of the IL-4
receptor chain (108) and inhibiting the secretion of
IL-12 (110). These functions of the HIV proteins may
contribute to the shift in cytokine profile as the infection progresses
toward the clinical picture of full-blown AIDS.
Human T-Lymphotropic Virus Type 1
Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus of the Oncovirinae subfamily. HTLV-1 infection is usually asymptomatic, but after a long latency period (approximately 30 years), it can cause adult T-cell lymphocytic leukemia (ATLL) or the non-oncogenic neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (103). These diseases can be attributed to the ability of HTLV-1 to infect Th cells and neurons, since these cell types express an as yet unidentified receptor for the virus. The histopathological picture of ATLL has the appearance of malignant monoclonal Th cells that are pleomorphic and contain lobulated nuclei. Although an elevated white blood cell count is typically seen, a state of immune suppression is associated with HTLV-1 infection in ATLL. On the other hand, immune stimulation appears to be associated with the pathology of demyelinization observed in HAM/TSP. Finally, in some rare cases, HTLV-1 affects other organs, causing dermatitis, pneumonitis, polymyositis, and uveitis (reference 102 and references therein).
During an HTLV-1 infection, a number of cytokines are produced,
including IL-1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-15,
TGF-, TNF-, TNF-1, IFN-, and GM-CSF (13, 22, 31, 55,
85, 99, 122, 161, 170, 172, 176, 227, 239, 258), as well as
chemokines such as IL-8, RANTES, and MIP-1 (14, 169).
Constitutive expression of the anti-inflammatory cytokine IL-10 has
been shown in ATLL cells and in HTLV-1-infected cell lines
(171), thus potentially explaining the state of immune suppression in ATLL. However, others have reported that HTLV-1 represses IL-10 expression (222), leaving this question
unresolved. TNF-, which has been associated with other inflammatory
diseases of the central nervous system, including multiple sclerosis,
encephalopathy secondary to AIDS, bacterial meningitis, and cerebral
malaria (133, 164, 245), has been demonstrated to cause
direct damage to oligodendrocytes and myelin in vitro (30,
225). Together with the observation that T cells infected by
HTLV-1 appear to express high levels of TNF- constitutively
(134), this cytokine seems to have a central position in
the neurological pathology of HTLV-1 infections.
For the mechanism of cytokine induction by HTLV-1, numerous studies have shown that the virally encoded Tax protein is by far the prime immune stimulator, regulating not only virus replication but also the expression of cellular genes encoding cytokines, chemokines, and their receptors (14, 55, 77, 109, 122, 234). Moreover, Tax-derived peptides constitute the majority of T-cell-recognized HTLV-1 epitopes (102). Signaling by intracellular Tax is very complex and has been extensively studied. Specific pathways will be described below where detailed knowledge is available.
First, Tax activates NF-B through the IKK pathway, resulting in
constitutive nuclear transcriptionally active NF-B (79, 144). Activation of IKK by Tax has been characterized and shown to involve IKK- and the kinase MEKK-1. Sun and colleges recently showed that a specific interaction between Tax and IKK- through leucine zipper domains is necessary for recruitment of Tax to the IKK
signalosome (88, 256). This recruitment is a prerequisite for IKK activation by Tax. Other studies have demonstrated a physical interaction between Tax and MEKK1, as well as an essential role of this
kinase in activation of the IKK signalosome by Tax (262). One interpretation of these results is that Tax, through interaction with IKK-, acts as a docking protein in the IKK signalosome
recruiting MEKK1 to the complex. This, in turn, triggers
MEKK1-dependent phosphorylation events, leading to activation of IKK
and eventually of NF-B.
Interestingly, several distinct NF-B-inducing pathways may be
activated by Tax. For instance, interaction between Tax and certain
isoforms of PKC (, 
and 
) results in the phosphorylation of
Tax and increased autophosphorylation of PKC. Together with the
observation that the PKC inhibitor calphostin C abrogates Tax-induced
NF-B DNA-binding activity, this indicates that Tax-activated PKC is
involved in NF-B activation (149). Whether this pathway involves IKK remains unresolved. Finally, it has been suggested that
Tax may activate NF-B through direct association with NF-B/Rel members. This hypothesis is based on the finding that Tax can interact
with p50, p65, c-Rel, and the precursor p100 under specified conditions
(21, 132, 136). The constitutive activation of NF-B is
believed to play a role in HTLV-1-mediated transformation of T cells as
seen in ATLL (126).
A second important transcription factor activated by Tax is ATF-2, which, together with the CREB transcription factor family, is involved in the activation of viral transcription through the CRE-like sites in the HTLV-1 LTR (75, 78). ATF-2 is a downstream target for the MAP kinases JNK and p38, and constitutively activated JNK has been found in leukocytes isolated from ATLL patients and associated with HTLV-1-mediated immortalization and tumorigenesis of infected T lymphocytes (257). In agreement with this observation are data showing activation of the transcription factor AP-1, one of the major downstream targets of JNK, in HTLV-1-infected lymphocytes (169).
Third, Tax activates NF-AT. It has long been known that NF-AT is essential for T-lymphocyte activation, and it has become clear that NF-AT also plays a role in HTLV-1 Tax-induced expression of several proteins, including IL-2 and Fas ligand (84, 85, 203), by binding to the CD28-responsive element in the promoters of these genes. While the exact mechanism remains unclear, it has been demonstrated that Tax induces a state of constitutive dephosphorylation and activation of NF-AT, thus implying that Tax may directly or indirectly activate the phosphatase calcineurin, which is the physiological upstream activator of NF-AT. This hypothesis is supported by the finding that the presence of cyclosporin A, a specific inhibitor of calcineurin, reverses the constitutive dephosphorylation and activation of NF-AT induced by Tax in HTLV-1-infected cells (84).
As discussed above, Tax activates several important signal transduction
pathways in infected cells, and the downstream targets include numerous
well-characterized transcription factors. Activation of transcription
factors by Tax does not necessarily involve activation of signal
transduction, however. For example, Tax expression has been reported to
enhance the DNA binding of CREB-2, C/EBP, and the Ets protein Spi-1
(PU.1), presumably through the ability of Tax to engage in
protein-protein interaction with these transcription factors (78,
239). In support of this notion, other studies have shown that
Tax, together with GATA-binding proteins (GBPs), facilitates DNA
recruitment of AP-1 and Ets proteins (22, 258).
Besides activating various intracellular signaling pathways in
HTLV-1-infected cells, Tax appears to function as an extracellular cytokine secreted from infected cells and affecting neuronal cells in a
paracrine manner (148). Extracellular soluble Tax induces NF-B activation and expression of immunoglobulin light chain, IL-2R, TNF-, TNF-, and IL-6 (28, 67, 148). The
intriguing observation that the presence of soluble Tax for as little
as 5 min is sufficient to induce TNF- production indicates that extracellular Tax may rapidly initiate a signal through a cellular surface receptor (55), whose nature remains unknown.
The current understanding of the molecular mechanisms of cytokine
induction by Tax illustrates that a wide range of signaling pathways
are involved. For instance, although Tax activates NF-B and CREB/ATF
family members, this is not sufficient to bring about IL-2 expression,
which in addition is dependent on the CD28-responsive element of the
IL-2 promoter and NF-AT (85). This was supported by
another study where a Tax mutant unable to activate NF-B was shown
to retain the capacity to induce the expression of IL-2 and GM-CSF
(99). By contrast, expression of IL-15 in response to Tax
is highly dependent on NF-B and a functional B site in the IL-15
promoter (13). The aberrant IL-5 expression and associated eosinophilia observed in many ATLL patients has been subjected to
careful molecular analysis. While one study showed that Tax cooperates
with GBPs and AP-1 for expression of IL-5 in ATLL cells (258), another group reported that Tax and GBPs also
synergize with Ets transcription factors for stimulation of IL-5
expression in Jurkat cells (22). Tax-induced IL-8
expression has also been studied molecularly and revealed to be
regulated by NF-B and AP-1 (169), which is similar to
what has been reported for other stimuli (260). AP-1 is
also involved in Tax-induced trans-activation of the
TGF-1 promoter (122). Finally, there is evidence that Tax stimulates IL-1 expression in human THP-1 cells. This was shown
to occur through a mechanism where Tax promotes the recruitment of
C/EBP and Spi-1 to the IL-1 promoter via protein-protein interactions (239).
In conclusion, HTLV-1 Tax-induced signal transduction and transformation have been extensively studied, and many aspects have been clarified. Several questions remain, however, one being the puzzling observation that HTLV-1 infection in some cases seems to result in immune stimulation, as seen in HAM/TSP, while in other cases it causes immune suppression, as observed in ATLL. A better understanding of cytokine production during HTLV-1 infection may help explain why one group of seropositive individuals develop leukemia, another develop a chronic neurologic disease, and yet another, the majority, remain clinically asymptomatic.
EXPERIMENTAL MODELS FOR VIRAL INFECTIONS
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Much of our knowledge about virus-cell interactions has been obtained through studies with various models for virus infections. Some of the most widely used viral models have been vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and Sendai virus. In addition, poly(I-C) has served as a very useful tool in studies of dsRNA accumulation, which is associated with many virus infections. In the following paragraphs, specific advances that have been achieved through the use of these model systems will be described.
IFN-/ have classically been described as the primary antiviral
compounds working in an auto- and paracrine fashion. Consequently, the
way in which IFN-/ is regulated during a virus infection has been
studied intensively. A series of studies have addressed the mechanism
through which the IFN- promoter is regulated in response to Sendai
virus and NDV infections. Various positive regulatory domains (PRDs)
have been identified in the human IFN- promoter. PRD I and III
interact with IRF family members, PRD II encompasses an NF-B-binding
site, while PRD IV binds ATF-2/c-Jun. The pattern that has emerged is
that while the promoter is only marginally inducible by either
transcription factor alone, a marked degree of synergy is observed when
all PRDs are occupied (123). This has led to the
enhanceosome theory, which suggests that maximal activation of
inducible promoters requires the assembly of a multiprotein complex,
which generates a surface with optimal interaction with the
transcription initiation machinery (37). This theory is supported by data showing that activation of the IFN- promoter is
dependent on recruitment of the transcriptional coactivators CBP and
p300 via a protein surface generated by NF-B, IRFs, and ATF-2/c-Jun
following binding to the promoter (162). In addition to
the above-described transcription factors, the architectural protein
high-mobility group I(Y) [HMG I(Y)] is part of the IFN- enhanceosome (123). HMG I(Y) is a DNA-binding protein that
recognizes AT-rich sequences. The role of HMG I(Y) in enhanceosome
assembly lies in the initial steps, where it facilitates the
recruitment of NF-B and ATF-2/c-Jun to the promoter by inducing
allosteric changes in the DNA conformation (261). Sendai
virus and NDV rapidly trigger activation of the IFN--inducing
transcription factors and hence the assembly of the enhanceosome and
subsequent high-output IFN- expression (250).
The IRF family member responsible for virus-induced IFN- expression
was first suggested to be IRF-1. This view was challenged by findings
with IRF-1 knockout mice, which showed an apparent unaltered ability to
produce IFN- during NDV infection (157). A series of
studies have now shown that IRF-3 and IRF-7 seem to be the IRF family
members involved in IFN-/ expression. Au et al. first showed that
IRF-3 was able to interact with IFN stimulation response elements,
which per se stimulated transcription only poorly (12).
Subsequently it was shown that NDV and Sendai virus infections trigger
the trans-activating potential of IRF-3, leading to
expression of IFN-4 and IFN- (155, 264). The
phosphorylation-dependent activation of IRF-3 is largely explained by
the interaction with CBP/p300. IRF-3, which prior to phosphorylation is
cytoplasmic and unable to interact with CBP/p300, gains this property
following phosphorylation and nuclear translocation and hence becomes
endowed with a trans-activating potential
(214). The virus-induced event that turns on IRF-3 is
activation of a serine/threonine kinase that phosphorylates the
carboxy-terminal region of IRF-3, allowing the protein to adapt an open
conformation and form dimers, which translocate to the nucleus and
activate transcription. The kinase responsible for phosphorylation of
IRF-3 has not been identified yet, but p38 has been suggested to be
involved in the activation of IRF-3 by lipopolysaccharide
(179), a component of the cell wall of gram-negative
bacteria. Activated IRF-3 stimulates the expression of IFN- (and
IFN-4), as described above. The resulting IFN in turn stimulates the
production of IRF-7, which remains cytoplasmic in uninfected cells and
becomes activated in virus-infected cells through a mechanism similar
to that used by IRF-3 (11). Activated IRF-3 and IRF-7 form
homo- and heterodimers. Following IRF-7 activation, transcription from
the IFN- non-4 promoters is up-regulated (155).
In addition to a role in IFN-/ expression, IRF-3 has been
reported to stimulate Sendai virus-induced RANTES transcription in the
human embryonic kidney cell line 293 (146). Future studies will show if the IRF-3/IRF-7 system plays a broader role in
virus-induced expression of cytokines and chemokines. This new field of
virus-induced signaling, which may represent a general mechanism in
host defense to virus infections, has at present been explored only
minimally beyond the model viruses, and it will be interesting to learn how the main human pathogenic viruses affect the IRF-3/IRF-7 system.
Poly(I-C) has been used extensively in experimental models mimicking
dsRNA intermediates accumulating during a virus infection. A viral
infection initiates a broad range of signals in the host cell, some of
which are ascribed to dsRNA accumulation. Our understanding of the
molecular events underlying these responses has grown significantly in
recent years, although many important questions have yet to be
answered. At present, dsRNA is known to activate NF-B, ATF-2/c-Jun, and IRF-3 (45, 251, 270), with the pathway leading to
activation of NF-B being the best described. Poly(I-C)/dsRNA has
been known for several years to activate the serine/threonine protein
kinase PKR, which is a major mediator of the antiviral and
antiproliferative activities of IFNs (254, 255). Following
binding of dsRNA, PKR undergoes autophosphorylation, resulting in
activation of PKR kinase activity and subsequent phosphorylation of
substrates. The best-studied substrate for PKR is the translational
initiation factor eIF-2, which is sequestered after phosphorylation,
eventually leading to inhibition of protein synthesis
(141). This renders PKR important in cell cycle
regulation, possibly by playing the role of a tumor suppressor.
Furthermore, PKR appears to play a broader role in the control of cell
proliferation and differentiation, tumor suppression, apoptosis, and
transcriptional regulation.
Williams and associates first showed that NF-B activation by dsRNA
is abrogated in PKR-deficient cell lines (130). Recently, Zamanian-Daryoush et al., from the same laboratory, demonstrated that
the dsRNA-induced signal is transmitted from PKR to NF-B through
IKK (270). The authors further presented data
suggesting that PKR may be part of the IKK signalosome and may play a
central role in NF-B activation by stimuli other than dsRNA. This
notion is supported by the observation that activation of NF-B by
Tat and TNF- is impaired in PKR-deficient cells (66,
270). Finally, NIK was identified in the signal transduction
pathway to NF-B between PKR and IKK. Essentially similar results
were obtained in a parallel study by Chu et al., who described that
NF-B activation by dsRNA or VSV was abrogated in IKK-deficient
cell lines (45). This latter study also addressed the role
of JNK and p38 in the response to dsRNA or VSV infection. The authors
were able to demonstrate involvement of JNK, but not p38, in
dsRNA-induced activation of ATF-2/c-Jun. Interestingly, PKR was found
not to be involved in VSV- or dsRNA-induced JNK activation. Similarly,
IRF-3 activation by dsRNA has also been found to be unaltered in
PKR-deficient cells (251). Taken together, these recent
data demonstrate in detail the pathway from dsRNA to NF-B
activation, involving the activation of PKR, which signals through NIK
and IKK, possibly via physical interaction with the IKK complex,
resulting in phosphorylation of the IKK subunit. This in turn
phosphorylates IB, eventually leading to the degradation of IB
and to nuclear translocation of NF-B. Identification of alternative
dsRNA-activated pathways, not involving PKR, are interesting new tasks
for this area in virus research.
CONCLUDING REMARKS
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Cytokines and chemokines play central roles in the host response
to viral infections as well as in the immunopathology associated with
many viral diseases. Within the last few years, significant advances
have been made in our understanding of the molecular mechanisms
governing the induction of cytokines and chemokines by viruses. By
interacting with specific cellular receptors, many viral glycoproteins
stimulate cells directly to secrete cytokines and chemokines. In
addition, viral RNA and a number of viral proteins with an
intracellular location interfere with cellular signal transduction and
transcription factor activity, thus promoting viral replication and
expression of proinflammatory proteins. Among the signaling pathways
activated by the viruses discussed in this review, NF-B seems to
play a particularly important role as far as expression of cytokines
and chemokines is concerned.
Some of the major challenges now facing this field of research are to deepen our understanding of virus-induced signaling and to unveil how this influences viral replication and cellular functions. Ultimately this knowledge could potentially be exploited to design drugs that specifically inhibit viral replication or reduce virus-induced immunopathology with minimal undesired effect for patients. In the past, experimental model systems for viral infections have proven useful and have provided important information that could subsequently be studied with the less manageable yet clinically more relevant viral human pathogens. The interplay between these approaches will also be used in the future as an important tool in studies of virus-host interactions.
ACKNOWLEDGMENTS
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This work was supported by grants from the Danish Health Science Research Council (grant 12-1622) and The Leo Research Foundation. T.H.M. was supported by a grant from the Danish Cancer Society.
FOOTNOTES
* Corresponding author. Mailing address: Department of Medical Microbiology and Immunology, Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark. Phone: (45) 8942 1767. Fax: (45) 8619 6128. E-mail: srp{at}microbiology.au.dk.
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Microbiology and Molecular Biology Reviews, March 2001, p. 131-150, Vol. 65, No. 1
1092-2172/01/$04.00+0 DOI: 10.1128/MMBR.65.1.131-150.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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