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

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related to the subsequent observation that neither virus infection nor interferon treatment after virus infection is able to generate the same spectrum of 20 ,50 oligoadenylates that are formed when mice are treated with both interferon and poly(I) poly(C) dsRNA. The products that accumulated during virus infection alone were mostly RNase L-inactive phosphorylated dimers; however, during combined interferon and poly(I) poly(C) treatment, the entire spectrum of RNase L-active phosphorylated molecules (dimer to pentamer) was present. These data implied that infection of mice with rabies virus causes both the induction and the activation of 2-5A synthetase, as does interferon and poly(I) poly(C) treatment.72,73 However, the intracellular products were different under different conditions. Virusinduced 2-5A synthetase seemed quite capable of synthesis of the longer 2-5A oligomers when evaluated in cell extracts, yet it was not able to bring about the synthesis of longer oligomers in the infected animal. This could be related simply to a difference in the 2-5A synthetase isoform present in the two conditions since it is now well-established that four isoforms (p40, p44, p69, p100) of IFN have been described,74 and they differ in response to dsRNA, salt, divalent cation, and soon in terms of the 2-5A product spectrum they generate. They are also differentially induced in vivo versus in vitro conditions. Schroder and co-workers75,76 reported that the nuclear matrix of HIV-infected as well as uninfected H9 (human T cells) contained 2-5A synthetase, which was increased by a factor of 7.7 in the HIV-infected cells. This latter increase was accompanied by a ve- to ten fold increase in 2-5A oligonucleotides in nuclei from HIV-1-infected H9 cells. Also increased in HIV-infected cells was an exonuclease activity that degraded 2-5A. The 2-5A-dependent RNase activity also underwent an increase to coincide with the time of maximum 2-5A synthetase activity. The RNase was also associated with the nuclear matrix as determined by photochemical cross-linking and probably was responsible for degradation of HIV transcripts. Failure of infected H9 cells to release HIV was correlated with the presence of high concentrations of 2-5A and high levels of the 2-5A-dependent RNase. When 2-5A concentration decreased, the cells began to release HIV. Treatment of cells with AZT (30 -azido-30 -deoxythymidine) extended the duration of time during which HIV transcript degradation occurred. Schroder et al.75,76 suggested that a useful approach to screen for potential chemotherapeutic agents for HIV would be to search for compounds that would act to stabilize the concentration of 2-5A in order to extend degradation of HIV transcripts. Thus, productive strategies for treating HIV infection using the 2-5A system may include the development of dsRNA analogues that increase 2-5A production, and nuclease-stable, phosphatase-stable, more potent 2-5A analogues. It remains to be established that this is a viable strategy that could be applied to HIV or any other RNA virus. In the absence of IFN treatment and when cells are infected with encephalomyocarditis virus (EMCV), a considerable decrease in RNase L occurs, but this decrease is prevented by pretreatment of the cells with IFN.57,77 Semliki Forest virus infection also results in inactivation of RNase L activity also by an unknown mechanism. This clearly represents a viral defense against one arm of the 2-5A system. The mechanism of this loss of RNase L activity is unknown and its
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RNA VIRUS NONSTRUCTURAL PROTEINS AS ANTAGONISTS OF INTERFERON ACTION
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occurrence in other RNA virus infections is largely unexplored, but probably is not related to the activity described below as RLI. Bisbal et al.78 83 isolated a polypeptide inhibitor (termed RLI) of the 2-5A system based on their screening of an expression library assayed by binding to radioactive 2-5ApCp. This protein was proposed as a regulator that would inhibit the binding of 2-5A to RNase L, thereby blocking activation of RNase L and its nuclease activity. Although RLI had a poor af nity for RNase L, it may associate directly but noncovalently with the enzyme to alter its activation potential by 2-5A. Overexpression of RLI in HeLa cells partly antagonized the anti-picornaviral effects of interferon, whereas RLI antisense constructs partly blocked downregulation of the 2-5A/RNase L pathway in EMCV-infected cells. RLI increased during human immunode ciency virus type 1 (HIV-1) infection. This might be related to the downregulation of RNase L activity that has been described previously. Overexpression of RLI caused a decrease in RNase L activity and a twofold enhancement of HIV production. The HIV replication increase correlated with enhancement of levels of HIV RNA and proteins. To the contrary, reduction of RLI levels in RLI antisense cDNA-expressing clones reversed the inhibition of RNase L activity associated with HIV multiplication and led to a threefold diminution in the viral load and a decrease in HIV RNA and proteins. ABCE homologues, subfamilies of ATP binding cassette (ABC) transporters, have been identi ed in 37 species that apparently lack an RNase L.84 ABCE is the proposed inhibitor of RNase L identi ed by Bisbal and co-workers. Thus, RNase L inhibition must not be the only functional role of ABCE. Indeed, it has been postulated that the ABCE protein may be necessary for the assembly of Gag polypeptides into immature HIV1 capsids.85 The role, if any, of ABCE proteins in other virus s replications and their interaction with elements of the interferon system remains unknown.
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17.4 RNA VIRUS NONSTRUCTURAL PROTEINS AS ANTAGONISTS OF INTERFERON ACTION The in uenza virus can express the NS1 protein, which binds double-stranded RNA.86 The NS1 protein represses the host cell antiviral response by several different mechanisms.86 93 These mechanisms include the inhibition of the IFNinducible double-stranded RNA-activated kinase PKR (protein kinase RNAregulated) and the blocking of IFN-b production by preventing NF-kB, IFN regulatory factor (IRF) 3, and IRF-7 activation. Indeed, the nonstructural (NS) gene segment of the 1918 in uenza virus has been evaluated to test the hypothesis that the enhanced virulence in 1918 could have been due to type I interferon inhibition by the NS1 protein. Most signi cantly, a virus containing the 1918 pandemic NS1 gene was more ef cient at blocking the expression of IFN-regulated genes than its parental in uenza A/WSN/33 virus.94,95 Bovine respiratory syncytial virus (BRSV) nonstructural proteins NS1 and NS2 cooperate to antagonize IFN-mediated antiviral mechanisms.96,97 Furthermore,
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