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

Generate QR in Visual Studio .NET VIRAL EVASION OF THE INTERFERON SYSTEM: NOVEL TARGETS FOR DRUG DISCOVERY
VIRAL EVASION OF THE INTERFERON SYSTEM: NOVEL TARGETS FOR DRUG DISCOVERY
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TABLE 17.2
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Virus Inhibition of PKR and OAS Virus/Viral Product Poxvirus E3L gene product (Refs. 10, 31 44), in uenza virus NS1 protein (Refs. 45 49), reovirus s3 and rotavirus NSP3 (reviewed in Ref. 20) Adenovirus VA1 transcript (reviewed in Ref. 20, hepatitis C virus NS5Aand E2 proteins (Refs. 50, 51), baculovirus PK2 protein (Ref. 52), poxvirus E3L [also OV20.0L (Ref. 38)], in uenza NS1, poxvirus K3L (Refs. 32, 34, 35), Epstein-Barr virus EBER1 and EBER2 transcripts (Ref. 45), HIV Tat protein, and TAR (Refs. 53, 54) Herpes simplex virus ICP34.5 protein (Ref. 55) Herpes simplex virus 20 50 A derivatives (Ref. 56), HIV-1 and encephalomyocarditis virus (Refs. 56, 57) Poliovirus (Refs. 58, 59)
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Target of Inhibition dsRNA binding/sequestering
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PKR binding
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PP1 (cellular protein phosphatase 1a) RNase L PKR degradation
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been reported to induce p58IPK, a cellular inhibitor of PKR.63 65,68 Poliovirus degrades PKR, possibly through transcriptional control,59 and herpes simplex virus (HSV) indirectly evades PKR by encoding the g1 ICP34.5 protein that interacts with cellular PP1 (protein phosphatase 1a).55 ICP34.5 redirects PP1 to phosphorylate and the eukaryotic initiation factor eIF2a subunit is able to be recycled and translation of proteins continues. All of the above viruses that encode products that are able to sequester dsRNA are also inhibitors of OAS, as dsRNA is required to activate this enzyme as well. 17.3 MODIFICATION OF 20 ,50 -OLIGOADENYLATES (2-5A) BY VIRAL DEFENSES AND OTHER EVASIONS OF RNase L The potency of 2-5A in inhibition of translation through activation of RNase L would seem to be a critical target for a virus to neutralize in some fashion. There appear to be at least two distinct mechanisms that can be teased out presently from existing studies. One involves the covalent modi cation of the highly active ppp50 (A20 p)n50 pA molecules. Another may be the generation of a protein inhibitor of RNase L. The latter molecule may or may not possess other virus-related functions. Of particular relevance to the discovery and development of poxvirus countermeasures would be the past observations from Ian Kerr s laboratory. Thus, Rice et al.69 found that vaccinia virus replication was relatively insensitive to the antiviral effects of interferon in mouse L929 and HeLa cells. Nonetheless, high concentrations of 2-5A (up to 5 mM) of 2-5A were found during vaccinia infection
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MODIFICATION OF 20 ,50 -OLIGOADENYLATES (2-5A) BY VIRAL DEFENSES
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of all of these types of cells treated at interferon concentrations too low to inhibit signi cantly the virus growth. High levels of 2-5A (up to 5 mM) also were found in non-interferon-treated HeLa cells (which have a high constitutive level of 2-5A synthetase) in which vaccinia virus replicates perfectly well. Rice et al.69 concluded that high levels of 2-5A per se have no necessary antiviral effect on vaccinia virus in these systems. HPLC analysis of the extracts of such cells revealed the presence of authentic 2-5A dimer, trimer, and tetramer 50 -triphosphates, 50 -dephosphorylated cores of the general formula A20 (50 pA20 )n50 pA (n 0 2), and a considerable number of unidenti ed compounds, some of which activated RNase L and some that did not. The role of these unidenti ed molecules in the insensitivity of vaccinia virus to interferon remains unknown. Paez and Estaeban70 also noted the resistance of vaccinia virus to interferon but obtained evidence that resistance was related to inhibition of the 2-5A system by intervention of a vaccinia viral ATPase (that would block production of 2-5A from the synthetase) and a viral phosphatase that would 50 -dephosphorylate biologically active 2-5A 50 -mono-, di-, and triphosphates. Similarly, novel oligoadenylates of unknown structure and unable to activate RNase L accumulate in interferon-treated SV-40 virus-infected monkey CV-1 cells.71 Some of the 20 ,50 -oligoadenylates corresponded to nonphosphorylated cores, (A20 p)nA, but a considerable amount eluted in the HPLC at retention times intermediate between ppp(A20 p)3A and cores. The unknown peaks did not seem to be changed upon digestion with alkaline phosphatase, implying the lack of terminal phosphate residues. Poly(I) poly(C) addition to interferon-treated CV-1 cells gave high levels of authentic biologically active 2-5A. In yet another apparent virus-related evasion of the 2-5A pathway, Cayley et al.56 noted that in human Chang cells herpes simplex viruses 1 and 2 (HSV-1 and HSV2) were much more resistant to interferon s antiviral action than was encephalomyocarditis virus. In all the above cases of interferon virus (HSV-1, HSV-2 or EMCV)-infected cells, similar amounts of 20 ,50 -oligoadenylates were synthesized, but in the instances of HSV-1 and HSV-2 infections, these oligoadenylates did not produce the characteristic RNase L activation footprints of ribosomal RNA cleavage. HPLC analysis of extracts from interferon, virus-infected cells showed that while RNase L-activating trimer ppp(A20 p)2A and tetramer ppp(A20 p)3A were present, there were also present apparent 20 ,50 -oligoadenylates that competed with the above 2-5A activators, but themselves were only weak activators of RNase L. These inhibitory compounds of unknown structure could account for the poor activation of RNase L and the relative resistance of HSV-1 and HSV-2 to interferon in Chang cells. One past observation is of special interest because the experiment was done in intact animals and involved an RNA virus rabies. IFN administered intravenously, subcutaneously, or intraperitoneally to mice crosses the blood brain barrier to cause enhanced levels of the two double-stranded RNA-dependent enzymes, the protein kinase and 20 ,50 -oligoadenylate (2-5A) synthetase in the brain.72,73 However, in spite of this effect, interferon seems to be unable to prevent the evolution of rabies disease in immunocompetent and immunosuppressed mice. This may be
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