Lethal Mutagenesis in Viruses and Its Effects

Öz

 Viruses are biological systems with wide variations in mutation rates. Viruses with highly accurate and conforming transcriptases have relatively low mutation rates. In contrast, viruses with high aberration transcriptases show high mutation rates, and high mutation rates can lead to higher genetic diversity. Viruses cannot be increased further without sacrificing by viral consistency according to the adaptive landscapes. A mutation can be defined as permanent changes that occur in the nucleotide sequence or the structure of nucleotides, often resulting in genetic material changes and structural disruption, thus, affect the polypeptide synthesis. Mutations can be created spontaneously or by physical-chemical properties. The nucleic acid mutations in viruses also determine their genome characteristics. Lethal mutagenesis is a broad-spectrum antiviral strategy that takes advantage of the high mutation rate and low mutation tolerance of many RNA viruses. Mutagenic drugs employ this strategy to increase the mutation rate of the virus, thus, leading a large number of mutations in the viral population, either lethal or highly harmful for continuesity of replication. Such an example Acyclovir (ACV), which is used for effective treatment in herpes simplex virus infections, works by blocking the thymidine kinase enzyme of the virus, only by entering the virus-infected cells. however, the virus developed resistance to this mechanism by generating mutant strains lacking thymidine kinase enzyme. In determining virus mutations, comparison with wild type is made phenotypically, but since it is very difficult to make this comparison in a genome that is found to be mutated frequently, making viral genome sequences has become a more effective method.

Anahtar Kelimeler

• Mutagenesis
• Virus
• Chemical

Kaynakça

1. Acevedo A, Brodsky L, Andino R (2014). Mutational and fitness landscapes of an RNA virus revealed through population sequencing. Nature 505, 686–690.
2. Bassi M R, Sempere R N, Meyn P, Polacek C, Arias A (2018). Extinction of Zika Virus and Usutu Virus by Lethal Mutagenesis Reveals Different Patterns of Sensitivity to Three Mutagenic Drugs Antimicrob Agents Chemother,27;62(9):e00380-18.
3. Bull J J, Sanjua´n R, Wilke O C (2007). Theory of lethal mutagenesis for viruses. J. Virol. 81:2930–2939.
4. Domingo-Calap P, Pereira-Gómez M, Sanjuán R (2012). Nucleoside Analogue Mutagenesis of a Single-Stranded DNA Virus: Evolution and Resistance J Virol, 86(18):9640-6.
5. Drake J W, Holland J J (1999). Mutation rates among RNA viruses. PNAS,23, 96(24) 13910-13913 Duffy S (2018). Why are RNA virus mutation rates so damn high. PLoS Biol 16:8.
6. Fonville J M, Wilks S H, James S L, Fox A, Ventresca M, Aban M, Xue L, Jones T C, Le N M H, Pham Q T (2014). Antibody landscapes after influenza virus infection or vaccination. Science 346(6212): 996–1000.
7. Graci J D, Harki D A, Korneeva V S, Edathil J P, Too K, Franco D, Smidansky E D, Paul AV, Peterson B R, Brown D M, Loakes D, Cameron C E (2007). Lethal mutagenesis of poliovirus mediated by a mutagenic pyrimidine analogue. J. Virol. 81:11256 –11266.
8. Graci J D, Too K, Smidansky E D, Edathil J P, Barr E W, Harki D A, Galarraga J E, Bollinger J M Jr, Peterson B R, Loakes D, Brown D M, Cameron C E (2008). Lethal mutagenesis of picornaviruses with N-6- modified purine nucleoside analogues. Antimicrob. Agents Chemother. 52:971–979.

9. Graci J D, Cameron C E (2006). Mechanisms of action of ribavirin against distinct viruses. Rev. Med. Virol. 16:37–48.
10. Morfin F, Thouvenot D (2003). Herpes simplex virus resistance to antiviral drugs. Journal of Clinical Virology 26:29-37.
11. Pauly M D, Lauring A S (2015). Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs J Virol,89(7): 3584-97.
12. Pfeiffer J K, Kirkegaard K (2003). A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. Proc. Natl. Acad. Sci. USA 100:7289–7294.
13. Rotem A, Serohijos A W R, Chang C B, Wolfe J T, Fischer A E, Mehoke T S, Zhang H, Tao Y, Ung W L, Choi J M, Rodrigues, J V, Kolawole A O, Koehler S A, Wu S, Thielen P M, Cui N, Demirev P A, Giacobbi N S, Julian T R, Schwab K, Lin J S, Smith T J, Pipas J M, Wobus C E, Feldman A B, Weitz D A, Shakhnovich E I (2018). Evolution on the Biophysical Fitness Landscape of an RNA Virus Mol. Biol. Evol. 35(10):2390–2400
14. Sanjua´n R, Domingo-Calap P (2016). Mechanisms of viral mutation Cell. Mol. Life Sci 73: 4433–4448.
15. Sanjuán R (2010). Mutational fitness effects in RNA and single-stranded DNA viruses: common patterns revealed by site-directed mutagenesis studies. Philos Trans R Soc Lond B Biol Sci. 27;365(1548):1975-82
16. Severson W E, Schmaljohn C S, Javadian A, Jonsson C B (2003). Ribavirin causes error catastrophe during Hantaan virus replication. J. Virol. 77:481–488
17. Sierra M, Airaksinen A, González-López C, Agudo R, Arias A, Domingo E (2007). Foot-and-mouth disease virus mutant with decreased sensitivity to ribavirin: implications for error catastrophe. J. Virol. 81: 2012–2024.
18. Sierra S, Da´vila M, Lowenstein P R, Domingo E (2000). Response of foot-and-mouth disease virus to increased mutagenesis: influence of viral load and fitness in loss of infectivity. J. Virol. 74:8316–8323
19. Tang J, Brixel R, Brune W (2019).Copy-Paste Mutagenesis: A Method for Large-Scale Alteration of Viral Genomes Int J Mol Sci. 20(4): 913.
20. Yang W, Wang Q, Howell KL, Lee J T, Cho D S (2005).ADAR1 RNA deaminase limits short interfering RNA efficacy in mammalian cells. J Biol Chem. 280:3946–3953.
21. Yeşilbağ K (2002). Mutational Changes and Importance in Veterinary Virology. Uludag Univ. J. Fac. Vet. Med. 21; 125-131
22. Zinshteyn B, Nishikura K (2009).Adenosine-to-inosine RNA editing Wiley Interdiscip Rev Syst Biol Med.1(2): 202–209.