Virus-Induced RNA

Gliotoxin (308) is a fungal metabolite, isolated from Aspergillus terreus and found to have antibacterial, antitumor and antifungal effects [18]. Gliotoxin acetate inhibited the CPE of poliovirus in monkey kidney cell cultures due to the early stage inhibition of RNA viral replication [18]. Gliotoxin also inhibits influenza virus-induced RNA polymerase. 

The antimetabolic activity of various unnatural amino acids has been investigated as a possible source of antiviral activity. Slight activity has been found in D-peniciUamine [250], D,L-thienylalanine [251] and selenocystine [252]. The last compound is claimed to be a specific inhibitor of virus induced RNA polymerase. 

Three virus-induced RNA structures can be isolated from the infected cells. They are ... 

From the beginning of the infectious cycle a small but defined fraction of the virus-induced RNAs is in a d-s form. At early times the ERas e-resist ant material accounts for not more than 0.5% of the virus-induced RRAs, but at the end of the cycle (6-8 hours post infection), the d-s molecules may represent up to 10% of the total ENA synthesized at that time. 

It was soon realized, however, that some kind of regulatory mechanism must intervene, because the synthesis of virus-induced RNAs was shown to be quite an asymmetrical process The bulk of the RNA found in the cytoplasm of picornavirus-infected cells is virion-like (i.e. "plus" strand), and only a very minor fraction of the newly synthesized RNA would hybridize to the RNA extracted from virions. Several explanations of this phenomenon have been offered ... 

Villareal, L. P., Breindl, M., and Holland, J. J., 1976, Determination of molar ratios of vesicular stomatitis virus induced RNA species in BHK21 cells. Biochemistry 15 1663. 

The notion that vaccinia virus-induced RNA may be involved in shut-off was independently proposed by Rosemond-Hombeak and Moss (1975) and Bablanian (1975). Rosemond-Hornbeak and Moss (1975) infected HeLa cell suspension cultures in the presence of 5-10 xg/ml of actinomycin D and showed that short poly(A)-rich RNAs were transcribed which sedimented a 5 S. Normal vaccinia virus transcripts sediment at 10-14 S (Becker and Joklik, 1964 Salzman et al.. 

Bablanian, R., Esteban, M., Baxt, B., and Sonnabend, J. A., 97Sa, Studies on the mechanisms of vaccinia virus cytopathic effects. I. Inhibition of protein synthesis in infected cells is associated with virus-induced RNA synthesis, J. Gen. Virol. 39 391. 

Studies have demonstrated that one such method is to examine the effects of disinfectants on endogenous RNA-dependent DNA polymerase (i.e. reverse transcriptase) activity. In essence, HIV is an RNA virus after it enters a cell the RNA is converted to DNA under the influence of reverse transcriptase. The virus induces a cytopathic effect on T lymphocytes, and in the assay reverse transcriptase activity is determined after exposure to different concentrations of various disinfectants. However, it has been suggested that monitoring residual viral reverse transcriptase activity is not a satisfactory alternative to tests whereby infectious HIV can be detected in systems employing fresh human peripheral blood mononuclear cells. 

The discovery of the base-paired, double-helical structure of deoxyribonucleic acid (DNA) provides the theoretic framework for determining how the information coded into DNA sequences is replicated and how these sequences direct the synthesis of ribonucleic acid (RNA) and proteins. Already clinical medicine has taken advantage of many of these discoveries, and the future promises much more. For example, the biochemistry of the nucleic acids is central to an understanding of virus-induced diseases, the immune re-sponse, the mechanism of action of drugs and antibiotics, and the spectrum of inherited diseases. 

Tam W, Hughes SH, Hayward WS et al. Avian bic, a gene isolated from a common retroviral site in avian leukosis virus-induced lymphomas that encodes a noncoding RNA, cooperates with c-myc in lymphomagenesis and erythroleukemogenesis. J Virol 2002 76 4275 286. 

Abelson Virus-Induced Lymphocytic Tumors. Abelson virus (A-MuLV or MuLV-A) is a type C RNA virus (25) and exists in the murine leukemia virus complex. This is a defective virus and contains the Moloney leukemia virus helper component and a replication-defective Abelson component (23) that transforms lymphocytes and 3T3 fibroblasts. While Abelson virus is not... 

Mice have been used extensively to examine virus host interactions, and to examine virus-induced encephalitis. The adaptive immune response plays a crucial role in controlling WNV infections in mice, including encephalitis (Diamond et al., 2003 Shresta and Diamond, 2004 Wang et al., 2003). WNV infection leads to a Toll-like receptor 3-dq3endent inflammatory response, which promotes brain penetration of the virus, neuronal injury, and enhanced encephalitis (Wang et al., 2004). Since Toll-like receptor 3 recognizes double-stranded RNA and promotes an innate immune response, this finding... 

The naturally occurring nucleoside analogues discussed in this section contain the IV-glycosyl linkage and either purine, pyrimidine, imidazole, diazepin, or indole rings. The purine nucleosides inhibit protein synthesis, RNA and DNA synthesis, and methyltransferases they have antimycoplasmal, antiviral, hypotensive, antifungal, antimycobacterial, and antitumor activities and induce sporulation (1—4). The pyrimidine nucleosides inhibit protein synthesis, virus replication, RNA and DNA synthesis, and cAMP phosphodiesterase. The imidazole nucleosides inhibit nucleic acid synthesis. The diazepin nucleosides inhibit adenosine deaminase (ADA). The indole nucleosides inhibit bacteria, yeast, fungi, and viruses. 

Other halogenated uridine derivatives have been reported to exhibit antiviral activity. Fluorodeoxyuridine has in vitro antiviral activity but is not used in clinical practice. Bromodeoxyuridine is used in subacute sclerosing panencephalitis, a deadly, virus-induced CNS disease. This agent appears to interfere with DNA synthesis in the same way as idoxuridine. The 5 -amino analogue of idoxuridine (5-iodo-5 -amino-2, 5 -dideoxyuridine) is a better antiviral agent than idoxuridine, and it is less toxic. It is metabolized in herpesvirus-infected cells only by thymidine kinase to di- and triphosphoramidates. These metabolites inhibit HSV-specific late RNA transcription, causing reduction of less infective abnormal viral proteins. 5-Bromo-2 -deoxyuridine has an action similar to that of other iodinated compounds. None of these compounds are commercially available in the United States. 

Interferon-alpha One of the type I interferons produced by peripheral blood leukocytes or lymphoblastoid cells when exposed to live or inactivated virus, double-stranded RNA, or bacterial products. It is the major interferon produced by virus-induced leukocyte cultures and, in addition to its pronounced antiviral activity, it causes activation of NK cells. [NIH]... 

Tam W, Ben-Yehuda D, Hayward WS 1997. bic, a novel gene activated by proviral insertions in avian leukosis virus-induced lymphomas, is Ukely to function through its noncoding RNA. Mol Cell Biol 17(3) 1490-1502. 

Clarke PA, Sharp NA, Clemens MJ. Translational control by the Epstein-Barr virus small RNA EBER-1. Reversal of the double-stranded RNA-induced inhibition of protein synthesis in reticulocyte lysates. EurJBiochem 1990 193(3)i635-641. 

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