Delayed Lysis Confers Resistance to the Nucleoside Analogue 5-Fluorouracil and Alleviates Mutation Accumulation in the Single-Stranded DNA Bacteriophage phi X174

作者：Pereira Gomez Marianoel; Sanjuan Rafael^*

来源：Journal of Virology, 2014, 88(9): 5042-5049.

DOI：10.1128/JVI.02147-13

Rates of spontaneous mutation determine viral fitness and adaptability. In RNA viruses, treatment with mutagenic nucleoside analogues selects for polymerase variants with increased fidelity, showing that viral mutation rates can be adjusted in response to imposed selective pressures. However, this type of resistance is not possible in viruses that do not encode their own polymerases, such as single-stranded DNA viruses. We previously showed that serial passaging of bacteriophage phi X174 in the presence of the nucleoside analogue 5-fluorouracil (5-FU) favored substitutions in the lysis protein E (P. Domingo-Calap, M. Pereira-Gomez, and R. Sanjun, J. Virol. 86: 9640-9646, 2012, doi: 10.1128/JVI.00613-12). Here, we found that approximately half (6/12) of the amino acid replacements in the N-terminal region of this protein led to delayed lysis, and two of these changes (V2A and D8A) also conferred partial resistance to 5-FU. By delaying lysis, the V2A and D8A substitutions allowed the virus to increase the burst size per cell in the presence of 5-FU. Furthermore, these substitutions tended to alleviate drug-induced mutagenesis by reducing the number of rounds of copying required for population growth, revealing a new mechanism of resistance. This form of mutation rate regulation may also be utilized by other viruses whose replication mode is similar to that of bacteriophage phi X174.

• 出版日期2014-5