@article{PAR00010320,
  title = {{R}andom codon re-encoding induces stable reduction of replicative fitness of {C}hikungunya virus in primate and mosquito cells},
  author = {{N}ougairede, {A}. and {D}e {F}abritus, {L}. and {A}ubry, {F}. and {G}ould, {E}. {A}. and {H}olmes, {E}. {C}. and de {L}amballerie, {X}avier},
  editor = {},
  language = {{ENG}},
  abstract = {{L}arge-scale codon re-encoding represents a powerful method of attenuating viruses to generate safe and cost-effective vaccines. {I}n contrast to specific approaches of codon re-encoding which modify genome-scale properties, we evaluated the effects of random codon re-encoding on the re-emerging human pathogen {C}hikungunya virus ({CHIKV}), and assessed the stability of the resultant viruses during serial in cellulo passage. {U}sing different combinations of three 1.4 kb randomly re-encoded regions located throughout the {CHIKV} genome six codon re-encoded viruses were obtained. {I}ntroducing a large number of slightly deleterious synonymous mutations reduced the replicative fitness of {CHIKV} in both primate and arthropod cells, demonstrating the impact of synonymous mutations on fitness. {D}ecrease of replicative fitness correlated with the extent of re-encoding, an observation that may assist in the modulation of viral attenuation. {T}he wild-type and two re-encoded viruses were passaged 50 times either in primate or insect cells, or in each cell line alternately. {T}hese viruses were analyzed using detailed fitness assays, complete genome sequences and the analysis of intra-population genetic diversity. {T}he response to codon re-encoding and adaptation to culture conditions occurred simultaneously, resulting in significant replicative fitness increases for both re-encoded and wild type viruses. {I}mportantly, however, the most re-encoded virus failed to recover its replicative fitness. {E}volution of these viruses in response to codon re-encoding was largely characterized by the emergence of both synonymous and non-synonymous mutations, sometimes located in genomic regions other than those involving re-encoding, and multiple convergent and compensatory mutations. {H}owever, there was a striking absence of codon reversion (<0.4%). {F}inally, multiple mutations were rapidly fixed in primate cells, whereas mosquito cells acted as a brake on evolution. {I}n conclusion, random codon re-encoding provides important information on the evolution and genetic stability of {CHIKV} viruses and could be exploited to develop a safe, live attenuated {CHIKV} vaccine.},
  keywords = {},
  booktitle = {},
  journal = {{P}los {P}athogens},
  volume = {9},
  numero = {2},
  pages = {e1003172},
  ISSN = {1553-7374},
  year = {2013},
  DOI = {10.1371/journal.ppat.1003172},
  URL = {https://www.documentation.ird.fr/hor/{PAR}00010320},
}