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Bioscience Horizons Advance Access originally published online on April 9, 2009
Bioscience Horizons 2009 2(2):212-224; doi:10.1093/biohorizons/hzp014
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Viral evasion of interferon stimulated genes

John A.L. Short*

Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK

* Corresponding author: John A. L. Short, 26 De Frene Road, Sydenham, London SE26 4AB, UK. Tel: +44 780 408 5575. Email: johnalshort{at}aol.com

Supervisor: Dr Andrew Macdonald, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.


   Abstract
Top
 Abstract
Introduction
 Viral Interference of the...
 PKR Degradation
 Discussion
 Conclusion
 Funding
 References
 Author Biography 
 
Viruses and their hosts since the dawn of time have been battling for supremacy. In recent years, the ‘Interferon Gateway’ encompassing interferon-alpha and -beta (IFN-{alpha}/β) expression, signalling and antiviral responses, has been uncovered. IFN-{alpha}/β are cytokines that co-ordinate the innate and adaptive immune responses to eliminate virus infections from the host. Interferon Stimulated Gene (ISG) products, such as protein kinase R, can prevent the translation of viral and cellular mRNAs to limit viral replication and can also initiate apoptosis if the cell is overwhelmed. In order to replicate, viruses have evolved viral evasion proteins that are able to target all aspects of the host response through a variety of sophisticated mechanisms. Viral evasion proteins can encode cellular domains to interact directly with ISGs and neutralize their function, hijack cellular pathways or degrade antiviral components. The high mutation rates associated with viral replication ensure that viruses will continue to adapt to our defences, but equally the viral evasion proteins are novel drug targets for eliminating or managing virus infections.

Key words: interferon, viral evasion, innate


   Introduction
Top
 Abstract
 Introduction
Viral Interference of the...
 PKR Degradation
 Discussion
 Conclusion
 Funding
 References
 Author Biography 
 
Viruses and their hosts have a dynamic relationship, constantly evolving strategies to outwit the other in a battle for survival. The host has evolved the innate and adaptive immune responses to eliminate virus infections. The innate response is the first line of defence. It uses an array of pattern recognition receptors (PRRs) to detect unique molecular patterns (PAMPS) associated with microorganisms.1 This initial immune response is rapid, which aims to either clear the infection or hold it at bay until an adaptive response is mounted. Historically, the innate response was considered to be simple and unimportant compared with the adaptive response. While the adaptive immune system is critical in eliminating specific virus infections, there has only recently been an awareness of how complex and critically important the innate response is for curbing viral replication.

The innate immune responses are interconnected and feed into the adaptive response via the action of interferons (IFNs), which act in an auto-, para- and endocrine manner2 (Fig. 1). The mass orchestration of the innate immune system is necessary to generate a sufficient response to neutralize the virus. IFNs are a class of cytokine that act as the ‘gatekeepers’ of innate and adaptive immunity, exhibiting a global influence on the action of antiviral extracellular and intracellular immune responses. The action of IFNs thus constitute a ‘Gateway’, orchestrating these responses to reduce or prevent virus replication and dissemination until the immune effecter cells eliminate the virus and infected cells.3


Figure 1
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  		Figure 1. The innate immune system matrix. When the virus penetrates the external barrier, it disseminates through the bloodstream or through tissues until it encounters its target cell, presenting various ligands that activate the extracellular and intracellular arms of the innate immune system (see text). Green dashed arrows indicate the target of cytokines produced. Pink dashed arrows show the target of IFN-{alpha}/β produced. Modified from Randall and Goodbourn,1 Goodbourn et al.,2 Unterholzner and Bowie60 and Pichlmair and Reis e Sousa.74

 
The molecular patterns of viruses are detected by various cellular sensors including Toll-like receptors and intracellular helicases (RIGI and MDA5). Binding of viral ligand activates signal transduction pathways that culminate in the expression of IFN-{alpha}/β. IFN-{alpha}/β activate the JAK/STAT pathway and induce transcription of interferon stimulated genes (ISGs).3 ISGs are expressed at low levels in nucleated cells so that the cell has some degree of response to a viral infection.1 The action of IFN induces an anti-viral state in infected and neighbouring cells hindering the virus lifecycle.

Protein kinase R. One of the first ISGs to be linked with an antiviral response was the double-stranded ribonucleic acid (dsRNA)-dependent Protein Kinase R (PKR). PKR is a serine/threonine kinase that is activated upon binding to viral dsRNA sourced either directly from viral genomes or from replication intermediates (Fig. 2). PKR has two domains: an amino-terminal regulatory dsRNA-binding domain and the carboxyl-terminal catalytic domain that contains conserved motifs that act on various transcription and translation factors.4


Figure 2
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  		Figure 2. The activation of PKR. Upon binding to viral dsRNA of at least 50 bp long, PKR undergoes a conformational change and autophosphoylates forming a dimer, which exposes the catalytic domain. The active PKR then phosphorylates eIF2{alpha} and IKKβ (see text). Green dashed arrows indicate phosphorylation. Modified from Randall and Goodbourn1 and Garcia et al.75

 
Elongation initiation factor-2 subunit alpha (eIF2{alpha}) is a critical translation cofactor required for the recruitment of initiator methionine Transfer RNA to ribosomes to form the translation pre-initiation complex. The nucleotide exchange factor eIF2B mediates the recycling of eIF2{alpha}, releasing it from the complex so that it can participate in the translation of other mRNAs. PKR phosphorylates eIF2{alpha} enabling it to irreversibly bind to the nucleotide exchange factor eIF2B. As eIF2B activity is inhibited by phosphorylated eIF2{alpha}, this ‘freezes’ eIF2{alpha} in the complex preventing it from initiating future translational events.5 This prevents the ribosomal translation of cellular and viral proteins, ultimately blocking viral replication in the cell.

PKR also mediates virus clearance by interacting with other components of the innate immune system. It can phosphorylate the protein kinase IKKβ (Figure 2). IKKβ then phosphorylates the nuclear factor {kappa}B (NF-{kappa}B) inhibitor (I{kappa}B), activating the NF-{kappa}B transcription factor. Dissociation and subsequent degradation of the phosphorylated inhibitor allows NF-{kappa}B to translocate to the nucleus. NF-{kappa}B is a master regulator of the expression of pro-inflammatory genes, e.g. inducing the expression of inflammatory cytokines such as tumour necrosis factor-{alpha} and Interleukin-6.6 Furthermore, PKR can activate cellular apoptosis pathways to destroy the cell before the virus can fully replicate and assemble.7

Endoribonuclease L (RNase L) instigates the degradation of viral and cellular mRNA to prevent viral protein synthesis. RNase L is activated by an interaction with adenosine oligomers. These oligomers are linked by a phosphodiester bond in a 2' to 5' configuration and are synthesized by 2'-5' oligoadenylate synthetase (2'-5' OAS), which is itself activated by binding to viral dsRNA.8 RNase L cleaves cellular and viral ssRNA and mRNA, inhibiting the translation of viral proteins.9 This mechanism operates using a positive feedback loop, whereby increasing amounts of viral dsRNA consequently activates additional RNase L. Viral overload results in the degradation of cellular RNA to such an extent that apoptotic pathways are activated to avert widespread viral dissemination.

More recently discovered antiviral proteins called restriction factors target specific steps of the virus lifecycle. Apolipoprotein B mRNA editing enzyme–catalytic polypeptide-like (APOBEC) involves both the cytidine deamination and subsequent mutation of the viral genome and the inhibition of reverse transcriptase activities (if applicable) to disrupt viral genome replication.10 Adenosine deaminase RNA 1 (ADAR-1) deaminates dsRNA viral replication intermediates. It replaces adenosines with inosine that causes the dsRNA to unwind disrupting viral replication.3 In contrast, tetherin is a cellular membrane protein that has been found to interact with the viral envelope of HIV by an undefined mechanism, obstructing viral release after assembly.11 These antivirals are critical for broad cellular targeting of all the viral lifecycle stages. By targeting multiple stages of the virus lifecycle, they minimize the possibility that a single virus evasion protein could disrupt all of their actions.

Promyelocytic leukaemia (PML) nuclear bodies are heterogeneous in size and composition, and contain the IFN-inducible protein PML and other IFN-{alpha}/β inducible proteins, such as Sp100. They play roles in transcriptional responses to stress and may regulate chromatin structure and promoter accessibility. Over-expression of certain isoforms of PML impair the replication of both RNA and DNA viruses, although the details of their involvement remain to be determined.12

Aims of the Review
Viruses have evolved various strategies to actively evade and subvert the host innate immune response, contributing to the vast expenditure and developmental failure of antivirals and antiviral therapies.13 Many viruses have adapted by expressing viral proteins that act as "keys", modulating the Interferon Gateway by ‘unlocking’ or inhibiting ISGs to enable viral replication and assembly in the cell. There has recently been a significant increase in our understanding of the pathways and effectors of the innate response that inhibit virus replication and therefore much is beyond the scope of this review. This review will focus on two established ISGs, PKR and RNase L and will also elaborate on the latest findings regarding novel antiviral proteins.


   Viral Interference of the ISGs: PKR
Top
 Abstract
 Introduction
 Viral Interference of the...
PKR Degradation
 Discussion
 Conclusion
 Funding
 References
 Author Biography 
 
The crucial importance of PKR in the antiviral response is highlighted by the observation that all classes of virus encode proteins target PKR function (Fig. 3). These include the DNA viruses, Vaccinia Virus (VACV), Adenovirus, Herpes Simplex virus (HSV) and Epstein–Barr Virus (EBV). The negative sense RNA viruses include Influenza A and Ebola Virus (EV) and the positive sense viruses include the Hepatitis C Virus (HCV) and Polio Virus. Presently, Rotavirus is the only known double-stranded RNA virus that targets PKR.


Figure 3
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  		Figure 3. Virus interference of PKR. Viruses are able to inhibit all stages of PKR activation and functionality (see text). Green dashed arrows indicate phosphorylation. Modified from Randall and Goodbourn,1 Unterholzner and Bowie,60 Balachandran and Barber76 and Langland et al.77

 
In order for PKR to be activated, it must first bind to viral dsRNA. VACV E3L, HSV US11, EBV EB2, Influenza A NS1, EV VP35 and Rotavirus Sigma3 virus evasion proteins are able to bind to viral dsRNA and sequester it from PKR. Thus, PKR remains inactive in the cell leading to continued viral protein translation and viral replication.

The HSV US11 dsRNA-binding domain is also able to bind to PKR in a dsRNA-independent manner to prevent PKR-mediated apoptosis of the cell. The necessity of this interaction evolved as the lytic cycle places the cell under stress, which activates cellular factors, including the PKR-activating protein (PACT).14 The critical nature of US11 is revealed in US11 knockout viruses, where PACT correctly binds to PKR and initiates the apoptotic cascade due, in part, to translational repression (Fig. 4). Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labelling and co-localization studies demonstrated that PACT still binds to PKR but the interaction of US11 with the RNA-binding domain disrupts the formation of the correct PKR conformation by PACT, preventing the initiation of apoptosis.


Figure 4
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  		Figure 4. HSV interference of dsRNA independent PKR activation. (A) In the absence of cellular viral stress signal, PKR is inactive where the kinase domain interacts with dsRNA-binding domain 2 (dsRBMII) preventing PACT from interacting with PKR. (B) Upon binding of cellular stress signal, the kinase domain changes conformation allowing PACT to bind to PKR, activating the kinase. (C) US11 C-terminus interacts with dsRBMI and dsRMBII, preventing PKR from changing fully conformation and being activated by PACT. Modified from Peters et al.14

 
Mutagenesis studies determined that the R-X-X-X-P motif of US11 is critical for binding to PKR.14 As the EBV EB2 protein contains this motif, it is possible that it shares the inhibitory properties of US11.

PKR Domain Interactions
Several viruses have evolved specialized mechanisms designed to inhibit the activity of PKR by expressing dsRNA homologues that bind directly to PKR (Fig. 5). Adenovirus encodes the virus-associated RNAs I and II (VAI and VAII) that are required for efficient translation of viral and cellular mRNAs late in infection.15 EBV encodes a small abundantly made transcript called EBER1. Not all PKR-binding RNAs are expressed as separate entities. The HCV internal ribosome entry site (IRES) is an integral component of the HCV-positive sense ssRNA viral genome. The HCV IRES recruits the 40S ribosome subunit and other cellular factors that are essential for translation of the HCV genome. The HCV IRES, Adenovirus VAI and EBV EBER1 contain extensive RNA secondary structures that interact with the PKR kinase domain impeding PKR kinase activity (Figure 5).


Figure 5
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  		Figure 5. The viral dsRNA homologues. The Adenovirus VAI, EBV EBER1 and HCV IRES viral products exhibit significant secondary structures where specific STEM loops are critical for PKR inhibition (see text). Modified from Ghadge et al.,15 Vyas et al.,16 Vuyisich et al.,17 Clarke and Mathews,19 Fok et al.,20 and Tumban et al.21

 
These homologues contain structural features that enable them to outcompete viral dsRNA for binding to the PKR dsRNA-binding region. The homologues do not have a 5' cap or 3' polyadenylated tail, but instead end in stretches of oligo-(U) that optimizes the efficiency of binding. The double-stranded stem loop regions of EBER1 STEM IV, the central domain STEM IV of VAI and STEM IIIb for the HCV IRES contain a highly conserved region that is involved in binding to the PKR dsRBMI domain.15–17 Protein-binding studies coupled with mutagenesis studies have determined that they contain a common motif of GGGU and ACCC that is critical for binding specifically to the dsRBMI domain18 (Fig. 6). It has recently been elucidated that the VAI apical stem forms a stable structure by interacting directly with the PKR dsRNA-binding region while the central domain contains the PKR inhibitory activity.19–23 The PKR kinase domain remains in an inactive state bound to dsRMBII, thereby allowing the continuation of cellular and viral protein synthesis.


Figure 6
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  		Figure 6. Viral interference of the PKR domains. Viral evasion proteins bind to specific domains of PKR (see text). Modified from Ghadge et al.,15 Vyas et al.16 and Vuyisich et al.17

 
Following the binding of viral dsRNA to PKR, dimerization is necessary for trans-autophosphoryation, which activates the kinase domain.24 HCV encodes two proteins: the non-structural NS5A and the E2 envelope glycoprotein that are able to block PKR dimerization. Certain genotypes of HCV contain a sequence within the NS5A protein termed the interferon sensitivity determining region (ISDR) that appears essential for the interaction with PKR. The presence of the ISDR is a virulence determinant, where those HCV genotypes that do not contain this region display significantly decreased pathology in infected individuals, with patients more likely to be successfully treated with IFN-{alpha}.25 Binding studies identified that the NS5A ISDR binds to the PKR autophosphorylation domain.26 Unglycoslated E2 envelope protein is localized in the cytosol where it can bind to the PKR eIF2{alpha} domain and prevent phosphorylation.27 As a result PKR autophosphoylation is prevented by NS5A and any activated PKR in the cytosol is immediately neutralized by E2, preventing PKR-mediated viral and cellular mRNA degradation.

Additionally, the HCV E2 protein can be post-translationally glycosylated in the rough endoplasmic reticulum (RER), where it can counteract the effect of the PKR-related kinase, PERK (PKR-like ER kinase).28, 29 PERK is activated upon RER stress, which can be caused by virus replication and virion morphogenesis. Activation of PERK results in the phosphorylation of eIF2{alpha}, thereby inhibiting cellular and viral protein synthesis. This can be prevented by E2 leading to continued viral replication.28

VACV encodes two proteins that bind to separate domains of PKR, thereby increasing the opportunity to inhibit PKR function. The VACV E3L protein binds to the eIF2{alpha} kinase domain.30 Mutagenesis studies revealed that E3L PKR inhibitory activity is dependent upon residues Lys 167 and Arg 168 contained within the E3L carboxyl-terminal dsRNA-binding domain. Furthermore, deletion of the amino-terminus of E3L reduced inhibition by 1000-fold, indicating that PKR inhibition requires an intact E3L protein.31 The VACV K3L protein binds to the PKR substrate recognition domain. Gene-sequencing studies determined that K3L shares 30% amino acid homology with the amino-terminus of eIF2{alpha}, containing the eIF2{alpha} PKR binding motif K-G-Y-I-D at position 72–83.32

Recent studies have shown that Human Herpes Virus 8 (HHV8) vIRF-2 and Influenza A NS1 protein inhibit PKR by mechanisms that remain to be elucidated. Protein-binding studies determined that vIRF-2 binds to the PKR dimerization domain while NS1 binds to the PKR regulatory domain.33

Not all viruses attempt to inhibit PKR activation. The human immunodeficiency virus-1 (HIV-1) requires an active PKR to enhance its own replication. HIV-1 encodes the Tat protein that is phosphorylated by PKR, enhancing the binding efficacy of Tat to HIV TAR RNA. The Tat/TAR interaction is crucial for HIV viral replication as it increases transcription of HIV mRNA. The phosphorylation of Tat at residues Ser 62, Tyr 64 and Ser 68 increases viral replication 100-fold compared with unphosphorylated Tat/TAR interactions.34 To evade the detrimental effects of PKR activation, Tat can also act as a pseudo-substrate of eIF2{alpha},35 although the mechanism by which HIV modulates the temporal activity of PKR remains poorly understood.


   PKR Degradation
Top
 Abstract
 Introduction
 Viral Interference of the...
 PKR Degradation
Discussion
 Conclusion
 Funding
 References
 Author Biography 
 
Interestingly, even viruses that utilize the ‘hit and run’ tactic for infection and often have short replication cycles still target PKR. Immunoprecipitation studies coupled with pulse-chase experiments revealed that the Picornavirus Poliovirus is able to degrade PKR, although the mechanism remains poorly defined.36 Protein-binding studies determined that the Poliovirus-encoded proteases 2A, 3C and 3CD are not involved in the degradation of PKR, suggesting that Poliovirus recruits a cellular protease or targets PKR for proteasomal degradation by encoding or recruiting an E3 ubiquitin ligase.

Viral Targeting of Phosphorylated eIF2{alpha}
Viruses can target phosphorylated eIF2{alpha} for dephosphorylation, inactivating the block on cellular and viral mRNA translation. In the early stages of HSV viral infection, HSV ICP34.5 protein performs this role by recruiting the cellular phosphatase protein phosphatase 1 alpha (PP1{alpha}), which dephosphorylates eIF2{alpha} (Fig. 7).


Figure 7
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  		Figure 7. Viral interference of eIF2{alpha} regulation. (A) In uninfected cells GADD34 recruits PP1{alpha} which dephosphorylates PeIF2{alpha} to prevent a block in cellular protein synthesis which is detrimental to the cell. (B) In virally infected cells, PKR phosphorylates eIF2{alpha}, inhibiting cellular and viral protein synthesis. (C) HSV ICP34.5 protein recruits PP1{alpha} which then dephosphorylates PeIF2{alpha}. (D) HPV E6 recruits GADD34 and PP1{alpha}, dephosphorylating PeIF2{alpha}. Green arrows show phosphorylation. Blue arrows show dephosphorylation. Modified from Cheng et al.37 and Kazemi et al.38

 
HSV ICP34.5 shares homology with the cellular regulator of PP1{alpha}, GADD34. In uninfected cells, GADD34 recruits PP1{alpha} to dephosphorylate eIF2{alpha}. This maintains a pool of unphosphorylated eIF2{alpha} that participates in the initiation of translation of cellular mRNAs. HSV ICP34.5 subverts this regulatory mechanism by mimicking GADD34 and directly recruits PP1{alpha} to eIF2{alpha}.37 This was demonstrated by cell infection studies where eIF2{alpha} remained phosphorylated and cellular and viral protein synthesis was blocked only in cells infected with dominant negative mutants of HSV ICP34.5.

Other DNA viruses including Human Papilloma Virus 18 (HPV18) have also evolved mechanisms to modulate PKR activity. Instead of encoding a homologue for GADD34, the HPV E6 protein acts as a platform for recruiting GADD34, which in turn recruits PP1{alpha} to dephosphorylate eIF2{alpha}.38 The mechanism utilized by E6 to promote this is currently unknown. The oncogenic HPV18 E6 protein is able to co-localize both in the nucleus and the cytosol as opposed to the benign HPV11 E6 protein, which is predominantly localized to the nucleus and is unable to promote eIF2{alpha} dephosphorylation.

RNase L
Viral dsRNA activates both PKR and a second pathway involving 2'-5' OAS that leads to the activation of RNase L and the shut down of translation and degradation of RNA. Just as viruses comprehensively inhibit PKR, they block the 2'-5' OAS RNase L activation pathway, either by expressing dsRNA-binding proteins as mentioned previously or by other mechanisms of action (Fig. 8). HSV-1 and -2 encode 2'-5' oligoadenylate homologues that directly compete with cellular 2'-5' oligoadenylate for RNase L. These 2'-5' OA derivatives are weak activators of RNase L, resulting in a profound decrease in RNase L activity in HSV-infected cells.39


Figure 8
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  		Figure 8. Viral inhibition of RNase L. Upon viral infection 2'-5' Oligoadenylate Synthetase (2'-5' OAS) binds to viral dsRNA. 2'-5'OAS converts ATP to 2'-5' linked oligoadenylates (2'-5' OA) which bind to RNase L, causing: (i) its dissociation from the RNase L Inhibitor (RLI) and (ii) RNase L dimerization. The active RNase L dimer degrades cellular and viral dsRNA. Like PKR viral inhibition, viruses target all stages in RNase L activation (see text). Modified from Bisbal and Silverman.78

 
HCV evades RNase L action through two different strategies. First, RNase L-mediated cleavage of HCV mRNA selects RNase L resistant variants.40 RNase L degrades HCV mRNA by cleaving predominantly after UA and UU dinucleotides in single-stranded regions. HCV mRNAs from IFN-{alpha} resistant genotypes (HCV 1a and 1b) have fewer UA and UU dinucleotides than those of IFN-{alpha}-sensitive genotypes (HCV 2a, 2b, 3a and 3b). Patients infected with HCV 1b viruses are cured less frequently than patients infected with HCV genotype 2 or 3. During IFN-{alpha} therapy, HCV 1b mRNA accumulates silent mutations preferentially at UA and UU dinucleotides, evading RNase L activity, and perhaps explaining the differences in pathogenicity between HCV genotypes.

Secondly, the HCV NS5A protein competes with viral dsRNA by binding to the active sites of 2'-5' OAS.41 Cell culture assays revealed that NS5A physically interacts with 2'-5' OAS, where mutagenesis studies elucidated that the amino-terminus of NS5A (a. a. 1–148) and two separate regions of 2'-5' OAS (a. a. 52–104 and 184–275) are necessary for this interaction. Virus rescue assays confirmed this observation and revealed that the NS5A carboxyl-terminal ISDR region and PKR-binding domain were not required.41

RNase L is inactive in cells infected with HIV-1, remaining bound to its inhibitor. Time course infection studies showed that HIV-1 induced the expression of the RNase L inhibitor (RLI) by an undefined mechanism.42 The RLI protein contains an ATP-binding cassette that forms a heterodimer with RNase L, inhibiting the binding of 2'-5' OA to RNase L in a non-competitive manner.43 The down-regulation of RNase L activity by HIV-1 contributes to the inhibition of the innate intracellular immune response and the inability of patients to clear HIV-1 infection.

Cellular Restriction Factors
Research into antiviral cellular restriction factors is a rapidly growing area, moving from structural analysis to the mechanisms of viral evasion. New factors are still being discovered as well as the scope and limitations of these factors in the antiviral response. APOBEC3G and the closely related APOCBEC3F are expressed mainly in T lymphocytes and macrophages, which are the main targets for infection with HIV. In cells infected with HIV mutants deficient for the accessory protein Vif, the APOBECs are packaged into HIV virions during viral assembly. During HIV reverse transcription, the APOBECs deaminate deoxycytidine residues to deoxyuridine (dU) in the growing minus-strand viral DNA.44 These dU-rich transcripts are either degraded or yield G-to-A hypermutated nonfunctional proviruses. Vif prevents the incorporation of the APOBECs into the virion by recruiting a cellular ubiquitin ligase (Cul 5), which targets the antiviral proteins for proteasomal degradation.45, 46

ADAR-1 is a member of the multigene family of RNA editing enzymes that catalyse the Carbon-6 deamination of adenosine (A) to yield inosine (I) in double-stranded RNA structures.47 VACV E3L protein disrupts this by binding to ADAR-1 via the E3L dsRNA binding domain, inhibiting ADAR-1 deaminase activity. As a result VACV prevents A-to-I editing by ADAR-1.48

In contrast to the intracellular restriction factors, tetherin is an integral cellular membrane protein, obstructing viral budding by binding to the HIV viral envelope.11 HIV can evade tetherin by encoding the Vpu accessory protein, which binds to tetherin and inhibits its activity by an undefined mechanism. A plausible explanation can be found by comparing Vpu with the HHV8 K5 protein, which reduces cellular levels of tetherin by targeting it for proteasomal-mediated degradation. Although Vpu has not yet been described to contain ubiquitin ligase activity, it may associate with a cellular ligase to accomplish this goal. Given the ability of tetherin to prevent viral budding, it is likely that many enveloped viruses are affected by tetherin, and have consequently evolved mechanisms to evade this.

Promyelocytic Leukaemia
Certain viruses induce the disruption of PML nuclear bodies by targeting PML for proteasome mediated degradation. PML interacts with and regulates p53, a cellular transcription factor necessary for the apoptosis pathway in response to cellular stress such as that associated with virus infection.49 HSV-1 targets PML in infected cells by utilising the ubiquitin ligase activity of ICP0 to degrade PMLs.50 Similar disruption of PML was observed in cells infected with other DNA viruses including EBV, HPV and Adenoviruses.51, 52 This suggests that DNA viruses disassemble PML either to prevent the induction of cellular apoptosis or that PMLs are perhaps needed for virus replication, but is yet to be proven.12

PML inhibition is not limited to DNA viruses, where both positive sense and negative sense RNA viruses such as HCV and Rabies Virus (RABV) display an equal level of interaction. Cell transfection assays demonstrate that the HCV core protein co-localizes with PML and p53.53 This indicates that the HCV core protein may compromise the pro-apoptotic function of p53, contributing to the formation of HCV-induced hepatocellular carcinoma. The RABV P protein binds to PML, subverting its localization from the nucleus to the cytosol.54 This enables PML sequestration from the nucleus inhibiting its antiviral activity, where consequently RABV replication is enhanced when compared with cells infected with RABV P negative mutants.


   Discussion
Top
 Abstract
 Introduction
 Viral Interference of the...
 PKR Degradation
 Discussion
Conclusion
 Funding
 References
 Author Biography 
 
The Interferon Gateway is the lynchpin of the innate host defence against virus infection. Without it, viruses would completely overwhelm the host before the adaptive immune system has the opportunity to respond. The antiviral state generated by the expression of ISGs, while it may not be able to eliminate the majority of pathogenic virus infections but is able to curtail virus dissemination through a variety of sophisticated mechanisms. Clearly, viruses that had not evolved ISG evasion strategies are now extinct. Consequently, we observe that both RNA and DNA viruses have developed an impressive array of mechanisms to surmount strategic components of ISG effecter pathways.

The Nature of Viral Inhibition
Viral evasion proteins expressed either separately or in combination are not able to completely disable ISGs, suggesting three possibilities. First, viral evasion proteins do not have the intrinsic capability to completely inhibit ISGs, but are still undergoing evolution to optimize this function. Secondly, the development of complete ISG inhibition by viral evasion proteins could be interpreted as a cellular stress signal activating other cellular antiviral responses. A complete shutdown of ISG activity could thus activate apoptotic cascades through unidentified regulator mechanisms, or activate further arms of the immune system. The latter has been observed in relation to HCV infection. Heat shock protein 70 protects cells against oxidative stress, and suppresses the activity of PKR and other related kinases such as PERK, as their activity is detrimental to the uninfected cell. IFN-{alpha} induces expression of Hsp70, preventing apoptosis in hepatic stellate cells by cytoxic T lymphocytes, which secrete type II IFN gamma, a potent inducer of the ISGs.55 Thus it would be detrimental for HCV replication if HCV viral evasion proteins orchestrated the complete inhibition of ISGs. Thirdly, it may not be beneficial to completely disrupt ISG activity as the virus could use this response as a means of regulating virus replication. Cell stress caused by an exorbitant high rate of viral replication could induce cellular apoptosis, killing the cell before the virus has a chance to assemble into a fully functioning virion.

Comparing RNA and DNA Viral Evasion Strategies
Viruses can inhibit multiple ISGs. By focusing on HCV, Influenza A, HSV and VACV, these offer prime case studies of the similarities and differences between RNA and DNA virus evasion strategies (Table 1). RNA viruses, despite having smaller genomes, are equally capable of inhibiting the ISGs. This is because both DNA and RNA viral evasion proteins use conserved functions to target the gateway. This is due in part to viruses facing a continuous downward selective pressure on genome size. The more viral evasion proteins a virus encodes the more time and resources it takes for the virus to replicate.56 Thus viruses containing fewer genes have a faster replication rate and can quickly outcompete virus species with a greater number of genes. However, this is balanced by the selective pressures applied by the host immune response. Those viral subspecies that can encode proteins to disrupt the action of cellular antivirals have a survival advantage over viruses that do not.


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  		Table 1. Viral case studies

 
Overall, the above selective pressures favour viral evasion proteins to contain two features: one is for viruses to encode a conserved mechanism whose mode of action is able to target multiple ISGs. Secondly, there is a selective pressure on individual proteins to contain as many of these conserved functions as possible within a single protein to minimize the genetic material required. Influenza A is a prime example, encoding the NS1 protein that inhibits the action of PKR by sequestering dsRNA and also by a dsRNA-independent mechanism. The HCV core protein is able to target PKR and 2'-5' OAS-binding domains. DNA viruses such as VACV and HSV encode dsRNA-binding proteins (E3L and US11, respectively) that exhibit the same function. Conservation of function is further observed where many viral evasion proteins originally evolved from those that are essential for viral replication and assembly. For example, the HCV E2 envelope glycoprotein is involved in initiating virus attachment to the host cell as well as inhibition PKR and PERK.

As DNA viruses can encode more genes, this allows for a greater complexity of the viral life style (e.g. latency) when compared with most RNA viruses that mainly cause acute infections such as Influenza A. For example, the HSV ICP34.5 protein is expressed early in infection before latency and integration into the genome. Once HSV enters the lytic cycle, a different subset of genes is expressed that includes US11 so that the virus is still able to inhibit PKR activation.57, 58 Thus the size of DNA viral genomes allows for the temporal regulation required for the complexity of their life cycle.

Antiviral Therapies
The prospect of developing novel antivirals using viral evasion proteins as targets has enormous potential in reducing the pathology of virus infections by aiding the immune system to clear viral infections. In addition, antivirals could also act as a prophylaxis to prevent further viral dissemination. Attenuated virus vaccines may be developed by isolating viruses that are unable to circumvent ISG activity. This may be achieved either by using reverse genetics to target known genes that encode viral ISG antagonists or by selecting mutants that are sensitive, e.g. Influenza A.59 Consequently, an alternative approach may be to select for point mutations that knock out the ISG antagonist function of the protein without affecting other functions.60 However, single point mutations raise the possibility that such attenuated viruses may revert to wild-type phenotypes.

The evolutionary mechanisms of DNA and RNA viruses may counter future antivirals developed whereby they could evolve novel strategies of evading the Interferon Gateway under selective pressure, making the therapy redundant. RNA viruses have high rates of mutation leading to the constant generation of many different strains due to virally encoded RNA polymerase or reverse transcriptase lacking error-correcting mechanisms.61 In consequence the emergence of escape mutants or a novel strain with an altered viral evasion protein could render the therapy ineffective. HIV is notorious for its high rate of genetic variability, forming many different quasi species in infected individuals and successfully eluding all vaccine attempts to date.62 Additionally, susceptible influenza viruses alter the therapeutic target by recombining with a resistant strain or species variant, or are simply replaced by resistant strains in the population, demonstrated by strain-specific human influenza vaccines being ineffective year on year.63 The change in viral evasion protein structure may also be brought about through gene segment recombination between different RNA viral strains, e.g. Influenza A.

In contrast, DNA viral genomes do not generally undergo such high rates of mutation as they use a host cellular DNA polymerase for their replication, which encodes an error-checking mechanism. However, it is difficult to develop antivirals for DNA viruses as they contain more viral evasion proteins than RNA viruses and can acquire additional cellular proteins that negate the effect of the antiviral. Adding to this difficulty is that many of the genes of DNA viruses have not been fully characterized, which suggests that further viral evasion proteins exist.

The Red Queen and Future Threats
The findings support the ‘Red Queen’ hypothesis where viruses and the host are continuously developing countermeasures to gain the evolutionary upper hand.64 The race is ongoing, where sometimes viruses develop mutations in viral proteins that allow emerging zoonotic viruses to cross species as illustrated by recent outbreaks of SARS-CoV, Hendra, Nipah and Ebola viruses, or the threat of transmission of avian H5N1 influenza to humans.65

The constant generation of novel viral strains and quasi species means that the existing viral pathogens could increase in virulence. As mentioned previously, certain HCV strains contain the ISDR region. This is due in part to the generation of viral quasi species in infected individuals. For example, in patients infected with the NS5A ISDR-negative HCV1b genotype, this strain evolved the ISDR region, under selective pressure, from PKR.66, 67 This illustrates that future variation in viral evasion proteins is possible and could contribute to more deadly pathogenic strains in the future.

The APOBECs and other restriction factors restrict certain specific variants of the immunodeficiency virus to specific species.68–72 However, this could change if viral evasion proteins acquire the mutations that confer the ability to evade immune restriction mechanisms. This concept has been displayed with Feline Immunodeficiency Virus (FIV) where genetic analysis of cheetah FIV-Ppa and leopard FIV-Aju revealed that the viruses were closely related despite the animals evolving from different felid lineages, suggesting recent inter-species transmission.73 This concept could thus occur (if it has not already) with other viruses between humans and other species.


   Conclusion
Top
 Abstract
 Introduction
 Viral Interference of the...
 PKR Degradation
 Discussion
 Conclusion
Funding
 References
 Author Biography 
 
In recent years the Interferon Gateway has been uncovered as the key portal of innate immunity. We have only just begun to understand the complex interplay between viruses and components of the Interferon Gateway such as ISGs. The rapid rate of viral evolution when compared with the vastly slower rate of human immune systems means that we will always face the peril of novel human pathogens emerging from other species and the return of viruses previously successfully cleared by our immune systems. That is why we must create additional weapons to enhance our armoury to counter past, present and future viral threats. However, the emergence of resistant strains to the selective pressures from ISGs and potential novel antiviral therapies would ensure that the arms race between humans and viruses continues.


   Funding
Top
 Abstract
 Introduction
 Viral Interference of the...
 PKR Degradation
 Discussion
 Conclusion
 Funding
References
 Author Biography 
 
This project was funded by the Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds.


   Acknowledgements
 
First and foremost I thank my supervisor Dr Andrew Macdonald for his comprehensive support and invaluable advice. Without him this would have been altogether a very different review! I also thank all the people from Microbial Culture Sciences at GlaxoSmithKline during my year in industry, who gave me many priceless tips towards writing up this project. Finally, I would also like to thank my personal tutor Professor Keith Holland for his encouragement and perspective.


   References
Top
 Abstract
 Introduction
 Viral Interference of the...
 PKR Degradation
 Discussion
 Conclusion
 Funding
 References
Author Biography 
 

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   Author Biography 
Top
 Abstract
 Introduction
 Viral Interference of the...
 PKR Degradation
 Discussion
 Conclusion
 Funding
 References
 Author Biography 
 
    John Short's degree course is Microbiology with Immunology. His chief interest is how pathogens and their hosts are able to interact with one another. John began a PhD in October 2009 based on ‘Comparisons between how influenza A viruses and paramyoviruses interact with the interferon system’ at the University of St. Andrews, under the supervision of Prof. Richard Randall. In the longer term, John hopes to become head of his own research group.
Submitted on 2 December 2008; accepted on 11 February 2009


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