key: cord-0976377-xs55np00
authors: Haller, O.; Weber, F.
title: Pathogenic Viruses: Smart Manipulators of the Interferon System
date: 2007
journal: Interferon: The 50th Anniversary
DOI: 10.1007/978-3-540-71329-6_15
sha: 8c4ba37e0ddaf223632ce51ca8507be79c8baec1
doc_id: 976377
cord_uid: xs55np00

Vertebrate cells are equipped with specialized receptors that sense the presence of viral nucleic acids and other conserved molecular signatures of infecting viruses. These sensing receptors are collectively called pattern recognition receptors (PRRs) and trigger the production of type I (α/β) interferons (IFNs).IFNs are secreted and establish a local and systemic antiviral state in responsive cells. Viruses, in turn, have evolved multiple strategies to escape the IFN system. They try to avoid PRR activation, inhibit IFN synthesis, bind and inactivate secreted IFN molecules, block IFN-activated signaling, or disturb the action of IFN-induced antiviral proteins. Here, we summarize current knowledge in light of most recent findings on the intricate interactions of viruses with the IFN system.

The type I IFN system provides a powerful and universal intracellular defense mechanism against viruses. Knockout mice that are defective in IFN signaling (Muller et al. 1994 ) quickly succumb to viral infections of all sorts (Bouloy et al. 2001; Bray 2001; Grieder and Vogel 1999; Hwang et al. 1995; Muller et al. 1994; Ryman et al. 2000; van den Broek et al. 1995) . Likewise, humans with genetic defects in interferon signaling die of viral disease at an early age (Dupuis et al. 2003) .

IFNs-α/β are synthesized by virus-infected tissue and specialized immune cells. After secretion into the extracellular space, these cytokines circulate in the body and cause susceptible cells to express potent antiviral mechanisms, thus limiting viral spread. Pathogenic viruses, however, have learned to manipulate the IFN system for their own sake. They have evolved efficient escape strategies allowing them to suppress IFN production, to modulate IFN signaling, and to block the action of antiviral effector proteins. This facet of the virus life cycle is only now being fully appreciated. Nevertheless, the first inklings of an anti-IFN activity were noticed early on, soon after the discovery of interferons by Isaacs and Lindenmann in 1957 (Isaacs and Lindenmann 1957) . Lindenmann himself made the surprising observation that infection of cells with a live virus inhibited the subsequent induction of IFN by an inactivated virus. This phenomenon was called inverse interference and was presumably the first description of a viral IFN-suppressive function (Lindenmann 1960) . Since then, great progress has been made in our understanding of how cells recognize viral intruders and how viruses manage to survive in the face of the powerful IFN system (for reviews see Garcia-Sastre and Biron 2006; Goodbourn et al. 2000; Haller et al. 2006 ).

It has become increasingly clear that conserved molecular signatures of viruses serve as danger signals that are recognized by specialized receptors of the host cell. These receptors are collectively called pattern recognition receptors (PRRs) because they recognize a diverse range of conserved pathogen-associated molecular patterns (PAMPs) found in infectious disease agents. The main PAMP of viruses appear to be nucleic acids, such as double-stranded RNA (dsRNA). The cellular PRRs designed to sense viruses can be divided into the extracellular/endosomal toll-like receptors (TLRs) (Akira and Takeda 2004; Bowie and Haga 2005) and the intracellular receptors RIG-I, MDA-5, and PKR (Meylan et al. 2006) . Signaling through these cellular sensors activates transcription of the IFN genes ( Fig. 1 ) . RIG-I and MDA-5 act trough the adaptor protein IPS-1/MAVS and the kinases TBK-1 and IKK-ε to activate the transcription factor IRF-3. A parallel pathway involves the dsRNA-binding kinase PKR, the TRAF adaptor molecules and the NF-κB kinase IKKα/β. Until very recently, it was assumed that the only molecule that clearly distinguishes viruses from their host (i.e., self vs nonself) is dsRNA, which would act as a danger signal capable of activating the IFN system. This concept was supported by data showing that many RNA and DNA viruses express proteins that bind this key molecule to avoid both IFN induction and activation of dsRNAdependent antiviral enzymes Langland et al. 2006) . Good examples are the NS1 protein of influenza A virus (Garcia-Sastre 2001 Lu et al. 1995; Min and Krug 2006) , the E3L protein of poxviruses (Hornemann et al. 2003; Xiang et al. 2002) , the VP35 protein of Ebola virus Hartman et al. 2006) , the sigma3 protein of reoviruses , and the US11 protein of herpes simplex virus (Mohr 2004; Poppers et al. 2000) . It came therefore as a surprise when it was realized that some viruses do not produce detectable amounts of dsRNA at all ). This unexpected finding indicated that cells must be able to sense other viral molecules important for IFN induction. Indeed, the cytoplasmic receptor RIG-I was subsequently found to bind to the 5′ end of certain viral ssRNA genomes provided they carried a 5′triphosphate group (Hornung et al. 2006; Pichlmair et al. 2006) . Such 5′ triphosphate moieties are usually not present on host RNA species in the cytoplasm and appear to provide an ideal recognition pattern for nonself. In line with this, it was shown that the NS1 of influenza A virus can bind ssRNA as well, and is able to form complexes with RIG-I (Mibayashi et al. 2006; Pichlmair et al. 2006) .

To subvert innate immunity, many viruses interfere with one or several steps in the IFN induction pathway. Figure 1 shows examples of viral antagonists that work at different levels of the signaling pathway. As mentioned above, the dsRNAbinding NS1 protein of influenza A virus binds to both dsRNA and ssRNA presumably by recognizing inter-or intramolecular dsRNA regions. Importantly, NS1 also associates with RIG-I in infected cells and seems to impair its signaling function (Mibayashi et al. 2006; Pichlmair et al. 2006) . In contrast, the V protein of paramyxovirus SV5 has no apparent RNA-binding activity. It inhibits IFN induction by targeting the RIG-I-related RNA sensor MDA-5 (Andrejeva et al. 2004; Childs et al. 2006) . Next in line is the adaptor protein IPS-1/MAVS, which connects the RNA sensors RIG-I and MDA5 with the IRF-3 kinases TBK-1/IKKε. It is specifically cleaved by the NS3-4A protease of hepatitis C virus (HCV) and additional flaviviruses (Chen et al. 2007; Lin et al. 2006; Meylan et al. 2005) (see also chapter by M. Gale, this volume). Activation of IRF-3 by TBK-1 is prevented by the phosphoprotein P of rabies virus (Brzozka et al. 2005 ) and the G1 glycoprotein of the hantavirus NY-1 (Alff et al. 2006 ). IRF-3 itself is degraded by the NPro proteins of pestiviruses such as classical swine fever virus and of bovine viral diarrhea virus La Rocca et al. 2005; Ruggli et al. 2005 ) via the proteasomal pathway (Bauhofer et al. 2007; . Also, the E6 protein of human papilloma virus 16 binds and inactivates IRF-3 (Ronco et al. 1998) . A sophisticated strategy to block IRF-3 is used by certain herpesviruses. Human herpes virus 8 (HHV-8), the causative agent of Kaposi sarcoma, expresses several IRF homologs, termed vIRFs, which exert a dominant-negative effect (Burysek et al. 1999a (Burysek et al. , 1999b Fuld et al. 2006; Li et al. 1998; Lubyova et al. 2004; Lubyova and Pitha 2000; Zimring et al. 1998) .

While these IFN subversion strategies show a degree of specificity and suggest an intimate co-evolution of viruses and their immunocompetent hosts, other and more basic mechanisms are also exploited by diverse viruses. For example, viruses with a lytic life cycle can afford to target the basic cellular transcription machinery and suppress IFN gene expression through a general shutoff of host gene transcription. For example, the nonstructural NSs proteins of bunyaviruses interfere with the basic cellular transcription machinery Le May et al. 2004; Thomas et al. 2004) . Although this strategy appears to be nonspecific, in vivo experiments with Rift Valley Fever virus (RVFV), Punta Toro virus, and Bunyamwera virus clearly demonstrated that the biological purpose of this broad-band shut-off is to inhibit IFN synthesis (Bouloy et al. 2001; Perrone et al. 2007; Weber et al. 2002) . The matrix (M) protein of vesicular stomatitis virus (VSV) is also a potent host cell shutoff factor that inhibits basal transcription (Yuan et al. 1998 ), impairs nuclear-cytoplasmic transport of RNAs and proteins (Her et al. 1997) , and inactivates translation factors (Connor and Lyles 2002) . As in the case of bunyavirus NSs, the biological significance of M-mediated shutoff is to suppress IFN induction upon VSV infection (Ferran and Lucas-Lenard 1997; Stojdl et al. 2003) . Likewise, proteinases of picornaviruses (e.g., foot and mouth disease virus, Theiler's virus, poliovirus) and pestiviruses (e.g., Classical Swine fever virus) cause a shutoff of the host cell metabolism to interfere with the IFN response (de Los Santos et al. 2006; Delhaye et al. 2004; Lyles 2000; Ruggli et al. 2003 Ruggli et al. , 2005 van Pesch et al. 2001) .

Finally, some viruses seem to use a stealth approach: they attempt to go undetected by the sensing machinery of the cell by either disguising or invading and replicating in hidden cellular compartments. SARS coronavirus and other members of the coronavirus family do not induce IFN in certain cell types (Cervantes- Barragan et al. 2006; Spiegel et al. 2005; Zhou and Perlman 2007) and are suspected to use such trickery (Stertz et al. 2007 ). In addition, SARS coronavirus expresses several proteins inhibiting IRF-3 and STAT1 (Kopecky-Bromberg et al. 2006) .

IFN-β and the various IFN-α subspecies bind to and activate a common type I IFN receptor (IFNAR), which signals to the nucleus through the so-called JAK-STAT pathway. This pathway is well characterized (Levy and Darnell 2002) and will not be described here in detail. It should be noted, however, that IFN signaling is highly regulated by cellular factors to avoid overstimulation of the system and keep a physiological balance. Negative feedback regulation is mainly mediated by IFN-induced members of the suppressor of the cytokine signaling protein (SOCS) family and the protein inhibitor of the activated STAT (PIAS) family. Essentially, SOCS members inhibit JAK tyrosine kinase activity, while PIAS members work as small ubiquitin-like modifier (SUMO) E3 ligases and inhibit transcriptional activity of activated STAT in the nucleus.

It has become increasingly clear that the IFN signal transduction pathway is also targeted by numerous viruses (Fig. 2 ) . Different approaches are used by different viruses according to their genetic capabilities.

A seemingly simple and highly preventive strategy is used by vaccinia and other poxviruses. They express soluble IFN-binding proteins to neutralize secreted IFN molecules Alcami et al. 2000; Puehler et al. 1998; Symons et al. 1995) . These so-called viroceptors prevent the establishment of an antiviral state as well as the autocrine IFN amplification loop, which normally leads to increased IFN production.

Most viruses cannot afford the luxury of encoding viroceptors. Instead they have evolved multifunctional proteins that specifically target select components of the IFN signaling cascade. In addition, some viruses exploit the cellular feedback loop to achieve the same result. A large number of viral proteins with anti-IFN properties have been described in the past few years, and we can discuss here only a few examples.

Members of the paramyxovirus family express up to three IFN-antagonistic proteins from the P gene (named P, C, and V) that interfere with JAK-STAT function. Depending on viral origin, these IFN antagonists act either by inhibiting the JAK kinases or by binding the STAT proteins, thereby sequestering them in high molecular mass complexes or inducing their proteasomal degradation (Andrejeva et al. 2002; Garcin et al. 2002; Gotoh et al. 2003; Nanda and Baron 2006; Palosaari et al. 2003; Parisien et al. 2001; Park et al. 2003; Rodriguez et al. 2003; Shaw et al. 2004 Shaw et al. , 2005 Takeuchi et al. 2001; Ulane et al. 2003; Yokota et al. 2003) . The P protein of rabies virus (a rhabdovirus) binds to tyrosine-phosphorylated STAT1 and STAT2 and retains the activated transcription factors in the cytoplasm, thereby preventing STAT-dependent expression of IFN-regulated genes . Interestingly, the paramyxoviral V protein as well as the rabies virus P protein have a dual anti-IFN function: they block both IFN induction (see above) and STAT signaling. Ebola virus, by contrast, uses a different protein, VP24, to block nuclear import of STAT by interacting with the transporter protein karyopherin alpha1 (Reid et al. 2006) . STAT signaling is also disturbed by viruses causing persistent infections, such as HCV (François et al. 2000; Heim et al. 1999 ), herpes simplex virus (HSV) (Chee and Roizman 2004; Yokota et al. 2004 ), HHV-8 (Fuld et al. 2006) , or cytomegalovirus (Khan et al. 2004; Zimmermann et al. 2005) .

As mentioned above, some viruses exploit the cellular feedback loop to inhibit IFN signaling. HSV type 1 (HSV-1) induces SOCS-3 to downregulate JAK and STAT phosphorylation (Yokota et al. 2004) . The core protein of HCV also appears to activate SOCS-3 (Bode et al. 2003) , while the virulence factor NSs of RVFV activates SOCS-1 to suppress IFN action (M. Bouloy, personal communication). Again, NSs seems to have a dual function since it also inhibits IFN production by blocking IFN gene transcription ). 

An efficient way to escape the IFN response is to directly inhibit the specific antiviral proteins that mediate the antiviral state. The targeting of IFN-induced proteins by viral counterplayers is a telling case for the importance of these effector molecules in antiviral defense and virus-host evolution.

To date, the best studied antiviral pathways are the protein kinase R (PKR) system Williams 1999) , the 2-5 OAS/RNaseL system (Silverman 1994) , and the Mx system (Haller and Kochs 2002) . Their importance for host survival following viral infections has been amply demonstrated (Arnheiter et al. 1996; Hefti et al. 1999; Zhou et al. 1999) . Additional proteins with known antiviral activities are P56 (Guo et al. 2000; Hui et al. 2003) , ISG20 (Espert et al. 2003) , promyelocytic leukemia protein (PML) (Regad et al. 2001 ), guanylatebinding protein 1 (GBP-1) (Anderson et al. 1999) , and RNA-specific adenosine deaminase 1 (ADAR1) (Samuel 2001) . Mx protein expression is tightly controlled by type I IFNs, making Mx gene expression a useful marker for IFN action in clinical settings (Antonelli et al. 1999; Roers et al. 1994) . In contrast, PKR and 2-5 OAS are constitutively expressed in a latent, inactive form in normal cells. Their expression is transcriptionally upregulated in IFN-treated cells. Importantly, these two enzymes need to be activated by viral dsRNA. This requirement makes them vulnerable to IFN antagonists found in many viruses. Indeed, viruses endowed with the capacity to sequester dsRNA by virtue of viral RNA-binding proteins are capable of preventing activation of PKR or the 2-5 OAS/RNaseL system (Antonelli et al. 1999; Roers et al. 1994; Weber et al. 2004 ). An alternative strategy used by several viruses is to encode small RNAs that compete with dsRNA for binding to PKR, thereby preventing activation. This is the case for adenoviruses (Mathews and Shenk 1991) , HCV (Vyas et al. 2003) , Epstein-Barr virus (EBV) (Elia et al. 1996) , and HIV-1 (Gunnery et al. 1990 ). Some viruses express proteins that either directly bind to or otherwise inactivate PKR. For example, the γ34.5 protein of HSV-1 triggers the dephosphorylation of eIF-2α, thus reverting the translational block established by PKR (He et al. 1997) . The E2 protein of HCV acts as pseudosubstrate for PKR (Taylor et al. 1999) , as does the Tat protein of HIV-1 (Roy et al. 1990) or the K3L protein of vaccinia virus (Davies et al. 1992) . Interestingly, FLUAV exploits a cellular pathway to block PKR in that it activates p58 IPK , a cellular inhibitor of PKR (Lee et al. 1990 ) and NS1 to block the 2-5 OAS/RNaseL system (Li et al. 2006; Min and Krug 2006) . Poliovirus induces the degradation of PKR (Black et al. 1993) . Many viruses also block the RNaseL pathway, either by expressing dsRNA-binding proteins (see above), or by other, more direct means. Encephalomyocarditis virus as well as HIV-1 induce the synthesis of RLI, a cellular RNaseL inhibitor (Martinand et al. 1998 (Martinand et al. , 1999 . Infection with HSV-1 and HSV-2 activates the synthesis of 2′-5′-oligoadenylate derivatives, which bind and prevent RNaseL activation (Cayley et al. 1984) . The antiviral effect of IFN is inhibited in cells infected with RSV (Atreya and Kulkarni 1999; Young et al. 2000) , an effect most probably mediated by the viral NS1 and the NS2 proteins (Schlender et al. 2000; Spann et al. 2004; Wright et al. 2006) .

Certain viruses induce the disruption of PML nuclear bodies (also called ND10) by proteasome-dependent degradation of PML and Sp100 (Moller and Schmitz 2003) . In HSV-1 infected cells, viral ICP0 accumulates in ND10 and induces the degradation of PML and Sp100, an activity that requires the E3 ligase activity of ICP0 (Boutell et al. 2002; Van Sant et al. 2001) . Similar disruptions of ND10 were observed in cells infected with CMV, EBV, HPV, and adenoviruses (Muller and Dejean 1999) . It is conceivable that viruses disassemble these nuclear structures to get rid of antiviral components, but sufficient data supporting this view are not yet available.

When considering the IFN-inducing and -suppressing activities of infecting viruses, it is important to keep in mind that the IFN response is generated in a cascade-like manner. As shown in Fig. 3 , viral replication and genome amplification leads to accumulation of viral nucleic acids and other components that are sensed as danger signals or PAMPs. They activate the IFN induction pathway (left part of Fig. 3 ) via cellular sensors (RIG-I, MDA-5), adaptors (IPS-1/ MAVS), protein kinases (TBK-1, IKK-ε), and transcription factors of the IFN regulatory factor (IRF) family (Honda and Taniguchi 2006) . IFN gene expression depends on the basic cellular transcription machinery composed of the cellular RNA polymerase II (RNAPII) and essential co-factors, such as components of the transcription factor IIH (TFIIH). Secreted IFNs bind to their cognate receptors and activate the JAK-STAT signaling pathway (right part of Fig. 3) , which induces the antiviral effector molecules. Most components of the IFN induction and signaling pathways are themselves IFN-inducible, representing a positive amplification loop. During viral replication, however, a number of viral IFN antagonists are produced (center part of Fig. 3) and interfere with the IFN response circuit. It is not unusual that a given virus displays more than one IFN-antagonistic protein and targets different parts of the IFN response pathway. Also, a single viral protein may inhibit quite different components of the IFN induction and signaling cascade. Thus, viral dsRNA-binding proteins have the advantage of blocking both IFN production and action. Besides, the dsRNA-binding NS1 protein of influenza A virus has additional functions and impairs also the post-transcriptional processing and nuclear export of cellular pre-mRNAs (Chen et al. 1999; Fortes et al. 1994; Kim et al. 2002; Li et al. 2001; Noah et al. 2003) . Since the IFN response is generated in a cascade-like manner, viral proteins blocking one component in this circuit also affect distant signaling or effector molecules, thereby amplifying the inhibitory effect. For example, JAK-STAT inhibitors suppress not only the production of antiviral proteins, but also the expression of RIG-I, MDA-5, IPS-1/MAVS, and IRFs, which are all IFN-inducible proteins. As a consequence, a negative amplification loop is produced, which further helps the virus to suppress the IFN system as a whole. 

Viruses are able to negatively influence the whole spectrum of the IFN response, often affecting different parts of the IFN circuit at the same time. The interplay between viruses and the IFN system, as described here, most likely results from an evolutionary race between the two genetic systems. The race is ongoing, as emerging viruses attempt transmission across species to new hosts. This is best illustrated by recent outbreaks of SARS coronavirus or the constant threat of avian influenza A viruses to invade the human population. Our present knowledge of the IFN system and viral countermeasures is still limited. Future research should provide better insight into the intricate interplay between viruses and the innate immune defenses of the host. This knowledge is important not only for a better understanding of viral pathogenesis, but also for designing novel vaccination strategies and therapeutic approaches.

Toll-like receptor signalling

Vaccinia, cowpox, and camelpox viruses encode soluble gamma interferon receptors with novel broad species specificity

The vaccinia virus soluble alpha/beta interferon (IFN) receptor binds to the cell surface and protects cells from the antiviral effects of IFN

The pathogenic NY-1 hantavirus G1 cytoplasmic tail inhibits RIG-I-and TBK-1-directed interferon responses

Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus

Degradation of STAT1 and STAT2 by the V proteins of simian virus 5 and human parainfluenza virus type 2, respectively: consequences for virus replication in the presence of alpha/beta and gamma interferons

The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter

Correlation of interferon-induced expression of MxA mRNA in peripheral blood mononuclear cells with the response of patients with chronic active hepatitis C to IFN-alpha therapy

Mx transgenic mice-animal models of health

Respiratory syncytial virus strain A2 is resistant to the antiviral effects of type I interferons and human MxA

Role of double-stranded RNA and Npro of classical swine fever virus in the activation of monocyte-derived dendritic cells

Npro of classical swine fever virus interacts with interferon regulatory factor 3 and induces its proteasomal degradation

NSs protein of Rift Valley Fever Virus blocks interferon production by inhibiting host gene transcription

Degradation of the interferon-induced 68,000-M(r) protein kinase by poliovirus requires RNA

Genetic evidence for an interferon-antagonistic function of rift valley fever virus nonstructural protein NSs

Herpes simplex virus type 1 immediate-early protein ICP0 and is isolated RING finger domain act as ubiquitin E3 ligases in vitro

The role of Toll-like receptors in the host response to viruses

The role of the Type I interferon response in the resistance of mice to filovirus infection

Identification of the rabies virus alpha/beta interferon antagonist: phosphoprotein P interferes with phosphorylation of interferon regulatory factor 3

Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2

Functional analysis of human herpesvirus 8-encoded viral interferon regulatory factor 1 and its association with cellular interferon regulatory factors and p300

Unique properties of a second human herpesvirus 8-encoded interferon regulatory factor (vIRF-2)

Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling

Activation of the ppp(A2'p)nA system in interferon-treated, herpes simplex virus-infected cells and evidence for novel inhibitors of the ppp(A2'p)nA-dependent RNase

Control of coronavirus infection through plasmacytoid dendritic cellderived type I interferon

Herpes simplex virus 1 gene products occlude the interferon signaling pathway at multiple sites

Influenza A virus NS1 protein targets poly(A)-binding protein II of the cellular 3′-end processing machinery

GB virus B disrupts RIG-I signaling by NS3/4A-mediated cleavage of the adaptor protein MAVS

mda-5, but not RIG-I, is a common target for paramyxovirus V proteins

Vesicular stomatitis virus infection alters the eIF4F translation initiation complex and causes dephosphorylation of the eIF4E binding protein 4E-BP

The vaccinia virus K3L gene product potentiates translation by inhibiting double-stranded-RNA-activated protein kinase and phosphorylation of the alpha subunit of eukaryotic initiation factor

The leader proteinase of foot-and-mouth disease virus inhibits the induction of beta interferon mRNA and blocks the host innate immune response

The leader protein of Theiler's virus interferes with nucleocytoplasmic trafficking of cellular proteins

Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency

Regulation of the doublestranded RNA-dependent protein kinase PKR by RNAs encoded by a repeated sequence in the Epstein-Barr virus genome

ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines an alternative antiviral pathway against RNA genomic viruses

The vesicular stomatitis virus matrix protein inhibits transcription from the human beta interferon promoter

Influenza virus NS1 protein inhibits pre-mRNA splicing and blocks mRNA nucleocytoplasmic transport

Expression of hepatitis C virus proteins interferes with the antiviral action of interferon independently of PKR-mediated control of protein synthesis

Inhibition of interferon signaling by the Kaposi's sarcoma-associated herpesvirus full-length viral interferon regulatory factor 2 protein

Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action

Inhibition of interferon-mediated antiviral responses by Influenza A viruses and other negative-strand RNA viruses

Type 1 interferons and the virus-host relationship: a lesson in detente

Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems

All four Sendai Virus C proteins bind Stat1, but only the larger forms also induce its mono-ubiquitination and degradation

Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures

The STAT2 activation process is a crucial target of Sendai virus C protein for the blockade of alpha interferon signaling

Role of interferon and interferon regulatory factors in early protection against Venezuelan equine encephalitis virus infection

Tat-responsive region RNA of human immunodeficiency virus 1 can prevent activation of the double-stranded-RNA-activated protein kinase

A new pathway of translational regulation mediated by eukaryotic initiation factor 3

Interferon-induced mx proteins: dynamin-like GTPases with antiviral activity

The interferon response circuit: induction and suppression by pathogenic viruses

Reverse genetic generation of recombinant Zaire Ebola viruses containing disrupted IRF-3 inhibitory domains results in attenuated virus growth in vitro and higher levels of IRF-3 activation without inhibiting viral transcription or replication

The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase

Human MxA protein protects mice lacking a functional alpha/beta interferon system against La Crosse virus and other lethal viral infections

Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway

Inhibition of Ran guanosine triphosphatasedependent nuclear transport by the matrix protein of vesicular stomatitis virus

The NPro product of bovine viral diarrhea virus inhibits DNA binding by interferon regulatory factor 3 and targets it for proteasomal degradation

IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors

Replication of modified vaccinia virus Ankara in primary chicken embryo fibroblasts requires expression of the interferon resistance gene E3L

) 5'-Triphosphate RNAIs the Ligand for RIG-I

Viral stress-inducible protein p56 inhibits translation by blocking the interaction of eIF3 with the ternary complex eIF2.GTPMet-tRNAi

A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses

Virus interference. I. The interferon

Reovirus sigma 3 protein: dsRNA binding and inhibition of RNA-activated protein kinase

Characterization of viral double-stranded RNA-binding proteins

A cytomegalovirus inhibitor of gamma interferon signaling controls immunoproteasome induction

Human influenza viruses activate an interferonindependent transcription of cellular antiviral genes: outcome with influenza A virus is unique

Severe acute respiratory syndrome coronavirus proteins open reading frame (Orf) 3b, Orf 6, and nucleocapsid function as interferon antagonists

Loss of interferon regulatory factor 3 in cells infected with classical swine fever virus involves the N-terminal protease Npro

Inhibition of PKR by RNA and DNA viruses

TFII H transcription factor, a target for the Rift Valley hemorrhagic fever virus

Purification and partial characterization of a cellular inhibitor of the interferon-induced protein kinase of Mr 68,000 from influenza virus-infected cells

Stats: transcriptional control and biological impact

Kaposi's sarcomaassociated herpesvirus viral interferon regulatory factor

Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA

The 3'-end-processing factor CPSF is required for the splicing of single-intron pre-mRNAs in vivo

Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKepsilon molecular complex from the mitochondrial outer membrane by hepatitis C virus NS3-4A proteolytic cleavage

Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the elF-2 translation initiation factor

Characterization of a novel human herpesvirus 8-encoded protein, vIRF-3, that shows homology to viral and cellular interferon regulatory factors

Kaposi's sarcoma-associated herpesvirus-encoded vIRF-3 stimulates the transcriptional activity of cellular IRF-3 and IRF-7

Cytopathogenesis and inhibition of host gene expression by RNA viruses

RNase L inhibitor (RLI) antisense constructions block partially the down regulation of the 2-5A/RNase L pathway in encephalomyocarditis-virus-(EMCV)-infected cells

RNase L inhibitor is induced during human immunodeficiency virus type 1 infection and down regulates the 2-5A/RNase L pathway in human T cells

Adenovirus virus-associated RNA and translation control

Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus

Intracellular pattern recognition receptors in the host response

Inhibition of retinoic acid-inducible gene-I-mediated induction of interferon-{beta} by the NS1 protein of influenza A virus

The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: inhibiting the 2'-5' oligo (A) synthetase/RNase L pathway

Neutralizing innate host defenses to control viral translation in HSV-1 infected cells

Viruses as hijackers of PML nuclear bodies

Viral immediate-early proteins abrogate the modification by SUMO-1 of PML and Sp100 proteins, correlating with nuclear body disruption

Functional role of type I and type II interferons in antiviral defense

Rinderpest virus blocks type I and type II interferon action: role of structural and nonstructural proteins

Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 3' end processing of cellular pre-mRNAS

STAT protein interference and suppression of cytokine signal transduction by measles virus V protein

The V protein of human parainfluenza virus 2 antagonizes type I interferon responses by destabilizing signal transducer and activator of transcription

Newcastle disease virus (NDV)-based assay demonstrates interferon-antagonist activity for the NDVV protein and the Nipah virus V, W, C proteins

The S segment of Punta Toro virus (Bunyaviridae Phlebovirus) is a major determinant of lethality in the Syrian hamster and codes for a type I interferon antagonist

RIG-I-mediated antiviral responses to single-stranded RNA bearing 5' phosphates

Inhibition of PKR activation by the proline-rich RNA binding domain of the herpes simplex virus type 1 Us11 protein

Vaccinia virus-encoded cytokine receptor binds and neutralizes chicken interferon-gamma

PML mediates the interferon-induced antiviral state against a complex retrovirus via its association with the viral transactivator

Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation

Hendra virus V protein inhibits interferon signaling by preventing STAT1 and STAT2 nuclear accumulation

MxA gene expression after live virus vaccination: a sensitive marker for endogenous type I interferon

Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity

Control of the interferon-induced 68-kilodalton protein kinase by the HIV-1 tat gene product

Classical swine fever virus interferes with cellular antiviral defense: evidence for a novel function of N(pro)

N(pro) of classical swine fever virus is an antagonist of double-stranded RNA-mediated apoptosis and IFN-alpha/beta induction

Alpha/beta interferon protects adult mice from fatal Sindbis virus infection and is an important determinant of cell and tissue tropism

Antiviral actions of interferons

Bovine respiratory syncytial virus nonstructural proteins NS1 and NS2 cooperatively antagonize alpha/beta interferon-induced antiviral response

Nipah virus V and W proteins have a common STAT1-binding domain yet inhibit STAT1 activation from the cytoplasmic and nuclear compartments, respectively

Nuclear localization of the Nipah virus W protein allows for inhibition of both virus-and toll-like receptor 3-triggered signaling pathways

Fascination with 2-5A-dependent RNase: a unique enzyme that functions in interferon action

Suppression of the induction of alpha, beta, and gamma interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages

Inhibition of Beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor

The intracellular sites of early replication and budding of SARScoronavirus

VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents

Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species specificity

Sendai virus C protein physically associates with Stat1

Inhibition of the interferoninducible protein kinase PKR by HCVE2 protein

Inhibition of RNA polymerase II phosphorylation by a viral interferon antagonist

STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling

Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors

The leader protein of Theiler's virus inhibits immediate-early alpha/beta interferon production

The infected cell protein 0 of herpes simplex virus 1 dynamically interacts with proteasomes, binds and activates the cdc34 E2 ubiquitin-conjugating enzyme, and possesses in vitro E3 ubiquitin ligase activity

Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA

Bunyamwera bunyavirus nonstructural protein NSs counteracts the induction of alpha/beta interferon

Inverse interference: how viruses fight the interferon system

Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses

PKR: a sentinel kinase for cellular stress

The interferon antagonist NS2 protein of respiratory syncytial virus is an important virulence determinant for humans

Blockade of interferon induction and action by the E3L double-stranded RNA binding proteins of vaccinia virus

Measles virus suppresses interferon-alpha signaling pathway: suppression of Jak1 phosphorylation and association of viral accessory proteins C and V, with interferon-alpha receptor complex

Induction of suppressor of cytokine signaling-3 by herpes simplex virus type 1 contributes to inhibition of the interferon signaling pathway

Paramyxoviridae use distinct virus-specific mechanisms to circumvent the interferon response

Inhibition of host RNA polymerase II-dependent transcription by vesicular stomatitis virus results from inactivation of TFIID

Interferon action in triply deficient mice reveals the existence of alternative antiviral pathways

Mouse hepatitis virus does not induce beta interferon synthesis and does not inhibit its induction by double-stranded RNA

A cytomegaloviral protein reveals a dual role for STAT2 in IFN-{gamma} signaling and antiviral responses

Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homolog that represses IRF-1-mediated transcription

We thank Peter Staeheli for critically reading the manuscript. Our own work described in the text was supported by grants from the Deutsche Forschungsgemeinschaft.