Mechanisms of viral emergence

Domingo, Esteban

The nucleic acid written in the first and third place in each of the four schemes is the one found in the parental and progeny viral particles. The nucleic acid in the middle position indicates the type of nucleic acid that acts as replicative intermediate (not the transcripts involved in gene expression that participate in the infectious cycle). The presence or not of RNA in the scheme determines the potential of genetic variation of the virus. RNA viruses and DNA viruses that have RNA as replicative intermediate (that is, viruses that follow replicative schemes 2, 3 and 4) display elevated mutation rates that have been estimated in 10 À3 to 10 À5 misincorporations per nucleotide copied [4, 14, 17] . The molecular basis for high mutation rates is the absence of a proofreading-repair activity in the viral RNA-dependent RNA polymerases (RdRp) and RNA-dependent DNA polymerases (RdDp) (also termed reverse transcriptases (RT)), evidenced by functional and structural studies [24, 52, 79] . There appear to be some exceptions to this rule, as suggested by the capacity of the influenza virus polymerase to remove excess GMP residues added to a capped oligonucleotide primer [37] , a 3 0 -end repair mechanism described in a satellite RNA of a plant virus [56] , and a 3 0 -5 0 exonuclease activity encoded by some coronaviruses [18, 54] . However, it has not been established whether the decrease in mutation rate promoted by such mechanisms has a major consequence for the biology of the corresponding viruses. In addition to the general absence of proofreadingrepair activities in RdRps and RdDps, the cellular post-replicative-repair pathways that act to correct mismatches in double-stranded DNA are not effective in repairing either doublestranded RNA or RNA-DNA hydrids [26] . Lack of proofreading-repair and post-replicative repair activities contributes decisively to high mutation rates of riboviruses, retroviruses and hepadnaviruses, a feature that has a profound influence in their biology [14] .