Delayed Lysis Confers Resistance to the Nucleoside Analogue 5-Fluorouracil and Alleviates Mutation Accumulation in the Single-Stranded DNA Bacteriophage ϕX174

摘要: ABSTRACT Rates of spontaneous mutation determine viral fitness and adaptability. In RNA viruses, treatment with mutagenic nucleoside analogues selects for polymerase variants increased fidelity, showing that rates can be adjusted in response to imposed selective pressures. However, this type resistance is not possible viruses do encode their own polymerases, such as single-stranded DNA viruses. We previously showed serial passaging bacteriophage ϕX174 the presence analogue 5-fluorouracil (5-FU) favored substitutions lysis protein E (P. Domingo-Calap, M. Pereira-Gomez, R. Sanjuan, J. Virol. 86: 9640–9646, 2012, doi:10.1128/JVI.00613–12). Here, we found approximately half (6/12) amino acid replacements N-terminal region led delayed lysis, two these changes (V2A D8A) also conferred partial 5-FU. By delaying V2A D8A allowed virus increase burst size per cell Furthermore, tended alleviate drug-induced mutagenesis by reducing number rounds copying required population growth, revealing a new mechanism resistance. This form rate regulation may utilized other whose replication mode similar ϕX174. IMPORTANCE Many display high mutations due defects proofreading or postreplicative repair, allowing them rapidly adapt changing environments. Viral have been optimized achieve adaptability without incurring an excessive genetic load. Supporting this, subjected chemical treatments shown evolve higher-fidelity polymerases. many cannot modulate fidelity because they polymerase. show regulating rates. that, under conditions, evolved amount progeny produced cell. As result, was amplified fewer infection cycles, chances appearance.