Replication of RNA Viruses

Li+ has significant inhibitory effects upon DNA viruses, in particular HSV which has been studied in depth. It was originally shown that Li+ inhibits viral replication in a dose-dependent, reversible manner in HSV-infected baby hamster kidney cells [240], and this has been found to be due to a Li+-induced decrease in the synthesis of viral DNA [241]. It is now well established that Li+ inhibits DNA synthesis in HSV types 1 and 2 and in several other DNA viruses, including measles, vaccinia, adenovirus, poxvirus, pseudorabies virus, Epstein-Barr virus, and the bovine, equine, and canine HV s [241]. Interestingly, Li+ has no effect on the replication of RNA viruses, such as influenza or encephalomyo-carditis virus. 

In addition, they assist in replication of RNA viruses, another process that requires RNA synthesis. Viruses sometimes make use of host RNA polymerases but often synthesize their own catalytic subunits. Bacteriophage T4 uses the E. coli RNA polymerase and o factors but modifies their action through the binding of several phage-encoded proteins.248 In contrast, phage T7 encodes its own relatively simple RNAP whose initiation complex (Section A,2)29 and elongation complexes have been studied 249-249b... 

Because viruses contain small genomes, study of transcription of viral DNA and of replication of RNA viruses has played an important role in helping us to understand transcription in eukaryotes 47/686-688 An example is the discovery of the virus SV40 enhancer, which has been discussed in Section C,4. Study of viral life cycles is also essential to future progress in fighting viral diseases. Each of the many different viruses has its own often very complex life cycle. Only a few details can be given here. For lucid summaries see Voyles.259... 

An enzyme that catalyzes the formation of DNA from an RNA template. This is an enzyme critical for the replication of RNA viruses such as HIV and is a major drag target for AIDS and other RNA viral diseases. See O Conner, T.E., Reverse transcriptase-progress, problems, and prospects, Bibl. Haematol. 39, 1165-1181, 1973 Wu, A.M. and Gallo, R.C., Reverse transcriptase, CRC Crit. Rev. Biochem. 3, 289-347, 1975 Verma, I.M., The... 

The bacterial siderophores parabactin and compound II secreted by Paracoccus denitrificans have been shown to inhibit the growth of leukaemia cells in culture and in experimental animals. They also appear capable of inhibiting the replication of RNA viruses. 

The flow of information in all cells is from DNA to RNA to protein, which is known as the central dogma of molecular biology it was formulated by Francis Crick shortly after the discovery of the structure of DNA. Information also can flow from DNA to DNA in both cells and among viruses that infect cells. Information also flows from RNA to RNA during the replication of RNA viruses such as the polio virus. The final permitted information transfer is from RNA to DNA, which only occurs in the case of retroviruses such as human immunodeficiency virus (HIV). The only information transfer that is prohibited by the central dogma is from protein to RNA or to DNA. The permitted information transfers in cells (infected or uninfected) is summarized below. 

Despite the availability of an effective HBV vaccine, the virus is still a major health problem with approximately 350 million persons infected worldwide. Hepatitis an infection of the liver that is caused by a variety of RNA viruses (hepatitis A virus, hepatitis B virus, hepatitis C virus). RNAi has been used to inhibit HBV replication both in vitro and in vivo (Carmona et al. 2006 Ely et al. 2008 Hamasaki et al. 2003 Klein et al. 2003 Konishi et al. 2003 Weinberg et al. 2007 Ying et al. 2003). HBV is a member of the Hepadnaviridae and its genome is a 3.2-kb double-stranded circular DNA. Synthetic siRNAs and shRNA expression constructs showed potent inhibition of HBV replication in mice (Chen et al. 2005, 2007 GUadi et al. 2003 McCaffrey et al. 2003 Morrissey et al. 2005b Shin et al. 2006 Wu et al. 2005b ... 

The group of RNA viruses to which HIV belongs are called retroviruses, because DNA is produced from RNA in their replication cycle—the reverse of the usual direction of transcription (DNA RNA). 

It exerts its action by inhibiting the replication of influenza virus, by inhibiting uncoating of viral RNA of influenza A within infected host cells. It is used in a dose of 200 mg/day in prevention of influenza A virus infection. 

The first step in the replication of influenza viruses, which takes place in the cytoplasm, is the synthesis of (+) strands that can serve both as mRNA for synthesis of proteins and as templates for synthesis of new (-) strands. Three of the capsid proteins form the required RNA polymerase. This "transcriptase" is primed preferentially by 5 -capped 10- to 13-nucleotide segments of RNA that have been cut by a viral nuclease from host mRNAs.700 The mRNAs made from viral RNA are polyadenylated and are translated by the host cell s ribosomes. However, some transcripts are used as templates to form viral (-) strands, which... 

Phosphonoformate is a pyrophosphate analog and inhibits both DNA polymerases and reverse transcriptase. However, toxicity may prevent longterm treatment of AIDS patients. Amantadine has a narrow antiviral specificity. It specifically inhibits initiation of the replication of influenza virus RNA of type A (but not of type B). Active only against retroviruses, 3 -azidothymidine is a reverse transcriptase inhibitor, which acts by a chain termination mechanism. It was synthesized in the early 1960s but only recently has been used in treatment of AIDS victims. More recently a series of 2, 3 -dideoxynucleosides, such as dideoxyinosine, have also been used.d Acyclic phosphonates, such as phosphonylmethoxypropyladenine, avoid the need for metabolic phosphorylation of the drug.6... 

Particularly relevant are studies on the replication of RNA-con-taining viruses, all of which have a double-stranded stage in their life cycles. Additionally, it may yield specific limited cleavages of such single-stranded RNA molecules as tRNA, ribosomal RNA, and phage RNA. Finally its ability to digest the RNA of DNA-RNA hybrids should provide a further measure of specificity in DNA-RNA hybridization experiments. ... 

The reproduction mechanism of Q(3, an RNA virus capable of infecting bacteria, is shown schematically in Fig. 1. During the replication of RNA,... 

The AIDS virus is a retrovirus that is, it stores its genetic information in the form of RNA. On infection it injects its RNA into the target cell and uses an enzyme called reverse transcriptase to synthesize DNA that is complementary to this RNA template. AZT is accepted by reverse transcriptase as a building block for this synthesis and slows or prevents the conversion of the viral RNA information into DNA. By disrupting this process, AZT slows the replication of the virus in the cell. The nucleoside analog 2, 3 -dideoxycytidine (DDC) works in a similar manner. Current treatments, which use a cocktail of two nucleoside analogs and a protease inhibitor, seem to at least slow the progress of the disease. 

The hepatitis delta virus (HDV) ribozyme is a member of the class of small ribozymes and functions as a self-cleaving RNA sequence critical to the replication of the virus RNA genome (1, 8, 40). HDV ribozymes are proposed to employ several catalytic strategies that include an important example of general acid/base catalysis that involves a specific cytosine residue in the active site. Indeed, a milestone in our understanding of RNA catalysis was the observation that HDV and other small ribozymes could function in the absence of divalent metal ion cofactors, provided that high (molar) concentrations of monovalent ions are present (41, 42). These high monovalent ion concentrations are believed to stabilize the active RNA conformation, which implies that the primary role of divalent metal ions is in structural stabilization (42). 

Lithium (at 40 mM) inhibits the replication of herpes virus, pox virus, and adenovirus (DNA viruses) but does not inhibit that of RNA viruses such as influenza virus or encephalomyocarditis virus (209). 

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