DNA-virus

Therapeutic potential of cidofouvir, (S)-l-[3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (HPMPC) for the treatment of DNA virus infections 98CCC480. 

Double stranded (ds) RNA is not a constituent of a normal cells but is produced during replication of many RNA and DNA viruses either as an obligatory intermediate or as a side product. As a foreign molecule, double stranded RNA induce the secretion of interferon (EFN) from lymphocytes, neutrophils and fibroblasts. 

Phillips, B., Abravaya, K., Morimoto, R.l. (1991), Analysis of the specificity and mechanism of the transcriptional activation of the human hsp70 gene during infection by DNA viruses. J. Virol. 11, 5680-5692. 

Fig. 2 Structural formulae of acyclic nucleoside phosphonates (anti-DNA virus and/or retrovirus agents)...

The prototype member of the ANPs is (5)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)adenine (HPMPA) (Fig. 2), first described for its broad-spectrum anti-DNA virus activity in 1986 (De Clercq et al. 1986). Then followed by the description of various other acyclic nucleoside phosphonates in 1987 (De Clercq et al. 1987). At present three acyclic nucleoside phosphonates have been licensed for clinical use cidofovir, adefovir, and tenofovir (Fig. 2). 

De Clercq E, Eield H J (2006) Antiviral prodrugs - the development of successful prodrug strategies for antiviral chemotherapy. Brit J Pharmacol 147 1-11 De Clercq E, Hol A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC (1986) A novel selective broad-spectrum anti-DNA virus agent. Nature 323 464 67 De Clercq E, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I, Hol A (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res 8 261-272... 

Ribavirin is a guanosine analog synthesized more than 35 years ago, which possesses broad-spectrum antiviral activity against several RNA and DNA viruses in vitro (Sidwell et al. 1972). When administered as monotherapy in patients with chronic hepatitis C, ribavirin induces a decline of serum alanine aminotransferase (ALT) levels while no effect on sustained virologic response is detectable (Di Bisceglie et al. 1992). 

DNA viruses Poxviruses Variola Vaccinia Large particles 200 x 250nm complex symmetry Variola is the smallpox virus. It produces a systemic infection with a characteristic vesicular rash affecting the face, arms and legs, and has a high mortality rate. Vaccinia has been derived from the cowpox virus and is used to immunize against smallpox... 

Methisazone (Fig. 5.2IB) inhibits DNA viruses (particularly vaccinia and variola) but not RNA viruses, and has been used in the prophylaxis of smallpox. It is now little used, especially as, according to the World Health Organization, smallpox has now been eradicated. 

There are a few key enzymes for the proliferation of human immunodeficiency virus (HIV). Reverse transcriptase is one of them since HIV is a member of the DNA viruses. Efavirenz (1) is an orally active non-nucleoside reverse transcriptase inhibitor (NNRTI) and was discovered at Merck Research Laboratories [1] for treatment of HIV infections. Efavirenz was originally licensed to DuPont Merck Pharmaceuticals which was later acquired by Bristol-Myers Squibb.11 The typical adult dose is 600 mg once a day and 1 is one of three key ingredients of the once-a-day oral HIV drug, Atripla (Figure 1.1). 

Albumin. Albumin is available in highly pure and uniform form, and exhibits low toxicity and good biological stability. It has been used as a carrier for methotrexate and a variety of antiviral drugs [amantadine, fioxuridine (5-fluorodeoxyuridine), and cytar-abine (cytosine arabinoside)] to treat macrophage tumors and infections caused by DNA viruses growing in macrophages. Heavily modified albumins are known... 

Figure 3.2 Relative sizes of some common viruses infecting humans. DNA viruses are green, RNA viruses are red.

Many bacterial viruses have genomes containing double-stranded DNA. Such viruses were the first bacterial viruses discovered, and have been the most extensively studied. With such a range of double-stranded DNA viruses, a wide variety of replication systems are present. In the present section, we discuss the best studied and most representative of the group, T4 and T7. The simpler, T7, will be discussed first. 

Bacteriophage T7 Bacteriophage T7 and its close relative T3 are relatively small DNA viruses that infect Escherichia coli. (Some strains of Shigella and Pasteurella are also hosts for phage T7.) The virus particle has an icosahedral head and a very small tail. The virus particle is fairly complex, with S different proteins in the head and 3-6 different proteins in the tail. One tail protein, the tail fiber protein, is the means by which the virus particle attaches to the bacterial cell surface. Only female cells of Escherichia coli can be infected with T7 male cells can be infected but the multiplication process is terminated during the latent period. 

We have discussed in a general way the nature of animal viruses in the first part of this chapter. Now we discuss in some detail the structure and molecular biology of a number of important animal viruses. Viruses will be discussed which illustrate different ways of replicating, and both RNA and DNA viruses will be covered. One group of animal viruses, those called the retroviruses, have both an RNA and a DNA phase of replication. Retroviruses are especially interesting not only because of their unusual mode of replication, but because retroviruses cause such important diseases as certain cancers and acquired immunodeficiency syndrome (AIDS). 

Similarly, the case for monophyly is hard to sustain for the origin of multicomponent (segmented) RNA viruses (positive single stranded RNA viruses, e.g. tobravirus, cucumovirus and bromovirus) and plant bipartite DNA viruses (single stranded DNA viruses, e.g. geminivirus) where coinfection ( two for one ) is required for the production of new virions (see Summary in Shostak, 1999). 

A dubious, but not uninteresting case can be made for mammalian herpesviruses, large double-stranded DNA viruses, which might have evolved from their mammalian hosts. Their nonstructural (enzymatic and control) viral proteins are similar to those of nonviral host proteins (McGeoch and Davidson, 1995), although recombination might also explain these similarities. 

McGeoch, D. J. and Davison A. J. (1995), Origins of DNA viruses , in A. J. Gibbs, C. H. Calisher and F. Garcia (Eds), Molecular Basis of Virus Evolution, Cambridge University Press, Cambridge,... 

Fogel, M. and Defendi, V. (1967) Infections of muscle cultures from various species with oncogenic DNA viruses (SV40 and Polyoma). Proceedings of the National... 

DNA viruses modulate the host immune response, e.g., most likely the etiologic agent of Kaposfs sarcoma, KSHV (human herpes vims —8), has captured complement-binding proteins, three cytokines (two macrophage inflammatory proteins and interleukin 6), bcl-2, interferon regulatory factors, interleukin 8 receptor. Certain retroviruses... 

Montone KT, Brigati DJ, Budgeon LR. Anatomic viral detection is automated the application of a robotic molecular pathology system for the detection of DNA viruses in anatomic pathology substrates, using immunocytochemical and nucleic acid hybridization techniques. Yale J. Biol. Med. 1989 62 141-158. 

DNA viruses, such as adenoviruses and papovaviruses (e.g. polyoma and SV40), induce cellular transformation in rodents. Other viruses have been implicated in human cancers. Epstein-Barr virus, for example, has been implicated with nasopharyngeal carcinoma, (3-cell lymphomas and Hodgkin s lymphoma. Human papilloma virus is linked to most cervical cancers. 

Additional viruses that may prove of some use as future viral vectors include adeno-associated virus and herpes virus. Adeno-associated virus is a very small, single-stranded DNA virus its genome consists of only two genes. It does not have the ability to replicate autonomously and can do so only in the presence of a co-infecting adenovirus (or other selected viruses). 

Nearly all classes of organisms studied exhibit physiological responses to the presence of Li+ and many of these are detailed in a review by Wissocq et al. including bacteria, viruses, amphibians, fish, birds, fungi, and higher plants [224], Of particular interest is the inhibitory action of Li+ upon DNA viruses and its efficacy in the treatment of herpes simplex virus (HS V). A recent review covering the possible mechanisms of action of Li+ in plants has also been published [225]. Below are merely a few examples to demonstrate the variety of the influences of Li+. 

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. 

---