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Extensive recoding of dengue virus type 2 specifically reduces replication in primate cells without gain-of-function in Aedes aegypti mosquitoes

By Charles B Stauft, Sam H. Shen, Yutong Song, Oleksandr Gorbatsevych, Emmanuel Asare, Bruce Futcher, Steffen Mueller, Anne Payne, Matthew Brecher, Laura Kramer, Eckard Wimmer

Posted 09 Jul 2018
bioRxiv DOI: 10.1101/365189 (published DOI: 10.1371/journal.pone.0198303)

Dengue virus (DENV), an arthropod-borne ("arbovirus") virus causing a range of human maladies ranging from self-limiting dengue fever to the life-threatening dengue shock syndrome, proliferates well in two different taxa of the Animal Kingdom, mosquitoes and primates. Unexpectedly, mosquitoes and primates have distinct preferences when expressing their genes by translation, e.g. members of these taxa show taxonomic group-specific intolerance to certain codon pairs. This is called "codon pair bias". By necessity, arboviruses evolved to delicately balance this fundamental difference in their ORFs. Using the mosquito-borne human pathogen DENV we have undone the evolutionarily conserved genomic balance in its ORF sequence and specifically shifted the encoding preference away from primates. However, this recoding of DENV raised concerns of 'gain-of-function,' namely whether recoding could inadvertently increase fitness for replication in the arthropod vector. Using mosquito cell cultures and two strains of Aedes aegypti we did not observe any increase in fitness in DENV2 variants codon pair deoptimized for humans. This ability to disrupt and control an arbovirus's host preference has great promise towards developing the next generation of synthetic vaccines not only for DENV but for other emerging arboviral pathogens such as chikungunya virus and Zika virus.

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