Models of RNA virus evolution and their roles in vaccine design

Ojosnegros, Samuel; Beerenwinkel, Niko

Since attenuated viruses may elicit a potent immune response without causing harm to the host, several strategies are being explored to obtain candidate viruses for LAVs, i.e., viruses displaying a reduced cell killing or replicative ability. Serial cytolytic transfers in cell culture tend to select viruses attenuated in the original host [160] . This is the case for FMDV or yellow fever virus among other viruses, and is currently an approved technique for several LAV preparations. Viruses selected after severe bottlenecks, such as serial plaque-to-plaque transfers, present a reduced fitness due to the accumulation of mutations associated with the Müller's ratchet effect [161, 162] . A new promising strategy for the attenuation of viruses is the rational design and synthesis of viral genomes with a strong codon bias. This approach has been implemented for Poliovirus and influenza virus [163, 164] . The viral genome synthesized encodes the same amino acid sequence as the wild type virus but encoded by infrequent codons in their host cells. Viruses harboring fidelity mutations in the replicase genes tend to produce a quasispecies of lower diversity and to be attenuated in vivo. This feature has also been employed to the rational design of a Poliovirus LAV [165] . Other strategies conceived to limit viral replication include the design of specific microRNAs or zinc finger nucleases targeting the viral genome [166] .