Viral evolution

Fig. 1 Three phases in viral evolution during suboptimal therapy. The black hne represents wild type virus, whereas the red line represents mutant virus (Res stands for the level of resistance and RC for replication capacity).

With increasing sequence data, there are now several bases on which to construct phylogenies. However, there is not yet a satisfactory phylogenetic classification that encompasses all viral families. Three-dimensional structure will continue to play a pivotal role as new viral families are explored. Such comparative studies are not just of academic importance. Beginning to understand the mechanisms of viral evolution is an important part of understanding how new viruses and their associated diseases emerge (Condit, 2001). 

Benson, S. D., Bamford, J. K., Bamford, D. H., and Burnett, R. M. (1999). Viral evolution revealed by bacteriophage PRDl and human adenovirus coat protein structures. Cell 98, 825-833. 

Sinkovics JG, Horvath JC. Kaposi s sarcoma breeding ground of htapesviridae A tour de force over viral evolution. Int J Oncol. 1999 14 615-646. Errata Idem 2005 27 5-47. Al-Attar S, Westra ER, van der Oost J, Brouns SJ. Qustered regularly interspersed shmt pahndromic repeats (ClSPRs) the hallmark of an ingenious antiviral defense mechanism in prokaryotes. Biol Chem. 2011 392 277-89. 

Short replication cycles that may be completed within a few hours, a large amount of viral progeny from one infected host-cell, as well as the general inaccuracy of viral nucleic acid polymerases result in an evolution occurring in fast motion, allowing rapid adaptation of viruses to selective pressures (see chapter by Boucher and Nijhius, this volume). Generalizing, it can be stated that any effective antiviral therapy will lead to the occurrence of resistance mutations. A well studied example... 

Abstract This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HlV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HlV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is Umited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufQciently ubiquitous that treating an acute infection would be... 

Antiviral Resistance and Impact on Viral Replication Capacity Evolution of Viruses Under Antiviral Pressure Occurs in Three Phases... 

In this chapter we describe the current insights into the evolution of viruses under pressure of antiviral therapy and the potential impact on viral fimess. As most recent work in this field has been done in the field of human immunodeficiency virus (HIV), we use the evolution of this virus as the basis for the chapter. Subsequently, we describe resistance evolution for Hepatitis B virus (HBV), where large progress has been made in recent years. Furthermore, we describe the resistance development for Hepatitis C virus (HCV), for which a very active drug development program is undertaken by several pharmaceutical companies. Finally, we discuss resistance evolution for Influenza. 

Our understanding of evolution and the role of viral diversity, resistance, and fitness has expanded greatly over the last decade, but is still incomplete. Undoubtedly, our insights will improve in the years to come. 

The evolution of antiviral resistance for viruses discussed in this chapter (HIV, HBV, HCV, and Influenza virus) shares some common features. Replication in vivo results in the generation of viral variation and selection of preexisting viruses from the population occurs under particular conditions. This will only happen when the escaping viruses have a sufficient level of both resistance and RC. In most cases, the resistance level subsequently increases further by the gradual acquisition of further mutations. Additional compensatory mutations then accumulate that help to restore full RC in the third stage. 

Merckel, M. C., Huiskonen, J. T., Bamford, D. H., Goldman, A., and Tuma, R. (2005). The structure of the bacteriophage PRD1 spike sheds light on the evolution of viral capsid architecture. Mol. Cell 18, 161-170. 

Retrotransposons lack an env gene and so cannot form viral particles. They can be thought of as defective viruses, trapped in cells. Comparisons between retroviruses and eukaryotic transposons suggest that reverse transcriptase is an ancient enzyme that predates the evolution of multicellular organisms. 

It is a commonly held belief that RNA preceded DNA in the early evolution of living systems. If this is the case then the first DNA polymerases must have been capable of transferring sequence information from RNA to DNA. Enzymes of this sort are called reverse transcriptases because they do the reverse of common transcriptases (see chapter 28). Reverse transcriptases no longer play the central role in genetic information transfer, but they are still found in all species and function in a number of capacities in both cellular and viral metabolism. 

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