VIRAL EVASION OF THE INTERFERON SYSTEM: NOVEL TARGETS FOR DRUG DISCOVERY in VS .NET

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VIRAL EVASION OF THE INTERFERON SYSTEM: NOVEL TARGETS FOR DRUG DISCOVERY
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and their functions, as inosine behaves like a guanosine. Thus, the number of mutant proteins in virus-infected cells is increased.8 Yet another class of proteins with antiviral activity induced by type I IFNs is the Mx proteins. Mx proteins are GTPases with enzymatic function, existing in multiple forms (cytoplasmic and nuclear). These proteins appear to associate with viral nucleocapsids from different virus families and inhibit their biological and transport properties, thus blocking viral replication.9 Whereas PKR and Mx genes are induced by type I IFNs, 2-5A synthetase (OAS) and RNase L are also induced by type II IFN, known as IFN-g.8 IFN-g has been shown to stimulate the production of nitric oxide and inhibit replication of ectromelia, vaccinia, and herpes simplex type-1 viruses in mouse macrophages.8 Inhibition of viral replication directly correlated to levels of nitric oxide synthetase.
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17.2 VIRUS COUNTERMEASURES FOR HOST DEFENSE MECHANISMS All of the preceding host defense mechanisms utilize cellular machinery in order to interfere with the replicative process of the virus. Translational arrest, induction of apoptosis, and introduction of mutations in proteins target the necessary replication of the virus vital to the establishment of infection. Evolving under these pressures from the host, viruses have developed an impressive arsenal to nullify these defenses. With high rates of evolution and packaging limitations, viruses have pirated host genes, modi ed and retained them to successfully propagate. The main focus of this piracy is to ensure production of viral proteins and reproduction of genetic material for the manufacture of viral progeny. With many products of the interferon system having a role in numerous cell pathways involved in apoptosis and translation of proteins, these pathways are the police and the prize of viral infection. What is this conundrum The virus must defeat the cell s machinery attempting to stop the production of viral proteins, yet parts of the cellular apparatus may be required for virus multiplication. At the same time, the cell must use its pathways that regulate cell proliferation to stop viral proliferation. Viruses vary in their ability to circumvent the host interferon response. In general, DNA viruses produce less dsRNA and initially are therefore less potent inducers of IFN.10 However, viral evasion tactics exist at much more sophisticated levels. Bray established the key role of type-1 IFN in the resistance of mice to the Ebola virus infection, showing that signi cant compromise of the interferon response gave rise to disease progress resembling that in primates.11 In line with these latter observations, Harcourt et al.12 found that induction of the major histocompatibility complex class I family of genes, OAS, interleukin-6 (IL-6), PKR, interferon (IFN) regulatory factor-1, and intercellular adhesion molecule-1 (ICAM-1) by dsRNA in human umbilical vein endothelial cells was suppressed by infection with the lovirus Ebola-Zaire. Likewise, Ebola and Marburg viruses each could infect dendritic cell cultures and support exponential viral replication without releasing
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VIRUS COUNTERMEASURES FOR HOST DEFENSE MECHANISMS
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TABLE 17.1
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Virus Inhibition of IFN Signaling and Transcription of ISGs Virus/Viral Product Human herpesvirus 8 IRF homologue (Ref. 16) human papillomavirus type 16 E7 protein (Ref. 17) Poxvirus soluble IFN receptor homologue (Refs. 18 21) Human cytomegalovirus (Refs. 22,23), murine polyomavirus T antigen (Ref. 24) Ebola virus VP35 (Ref. 15) Dengue virus (Refs. 11 15), paramyxovirus, simian virus 5 V protein (Refs. 25, 26), mumps virus (Ref. 27), human parain uenza virus 2 (Ref. 28), adenovirus E1A protein (Ref. 29) Hepatitis B virus nucleocapsid protein (Ref. 30)
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Target of Inhibition ISG transcription IFNs binding to receptors JAK and/or p48 expression IRF 3 STAT and/or p48
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interferon-a (IFN-a).13 In addition, such cultures were impaired in IFN-a production if treated with dsRNA that normally should lead to IFN production.13 Basler et al.14 reported that Ebola virus protein VP35 blocked dsRNA- and virus-mediated induction of the IFN-stimulated response element reporter gene and also inhibited dsRNA- and virus-mediated induction of the IFN-b promoter. Moreover, Ebola virus VP35 protein inhibits activation of the interferon regulatory factor-3 (IRF-3), a key component in the initiation of the host cell interferon response, through inhibition of IRF-3 phosphorylation.15 IRF-3 subsequently cannot dimerize and translocate to the nucleus. Dengue virus nonstructural proteins NS2A, NS4B, and NS4A have been shown to downregulate IFN-b-stimulated gene.19 Table 17.1 shows the mechanism of action and inhibition for some viruses that target the signaling and transcriptional responses of IFNs. Viruses have evolved mechanisms that target products of the IFN pathway and render them ineffective. Two products that have been extensively researched are PKR and OAS. Table 17.2 lists some viruses that inhibit PKR and OAS and are able to reproduce in the face of the host cell s defenses. These processes are discussed below. The importance of PKR in mounting an antiviral defense can be attested to by the numerous viral mechanisms devoted to inhibit this activity. Viruses that encode proteins to bind to and sequester dsRNA prevent the activation of PKR indirectly. Poxviruses (vaccinia, ectromelia, cowpox, and camelpox) encode a gene product E3L that contains a dsRNA binding domain and inhibits PKR.8,31,33,34,36,39 43,60 65 The orf virus OV20.0L gene product is 33% homologous to E3L and presumably contributes to interferon evasion by the same mechanism.38,66,67 Many viruses also encode products that actively bind to PKR and thus inhibit its activity. Adenovirus (AV), Epstein-Barr virus (EBV), and human immunode ciency virus type 1 (HIV-1) all encode small RNA transcripts that bind to the active site for dsRNA binding.20,45,53,54 In uenza virus NS1 protein binds directly to PKR but has also
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