Attenuation of dengue (and other RNA viruses) with codon pair recoding can be explained by increased CpG/UpA dinucleotide frequencies

Shen et al. (1) describe the modification of three regions of the Dengue virus type 2 (DENV-2) genome to match the codon pair use of insect genes rather than those of mammals. We have previously shown that such recoding also modifies frequencies of CpG and UpA dinucleotides and have proposed it is this, rather than codon pair use, that restricts replication in mammalian cells (2). We argue that DENV-2 mutants are attenuated for cell culture and in vivo replication in mice through the same mechanism. Our conclusions are based on the following observations.