Mechanisms of viral emergence

Domingo, Esteban

Regarding the role of genetic variation, there are several possibilities to explain a successful introduction of a virus into a new host species. The main ones are: (1) the virus is competent to replicate equally well in the donor host species and in the recipient new host species. No genetic variation for the change of host range is needed. The reason why the emergence did not occur before is that either the encounter between the two hosts had not occurred until then, or that a threshold dose of virus needed for the successful introduction had not been attained in past encounters. Such a threshold amount of virus can be imposed by limited virus particle stability, the immune response of the recipient host, and other factors. (2) The virus is not efficient in replicating in the new host, and genetic variation of the virus must intervene to achieve a successful introduction. In this case, again, several factors come into play. They are briefly described here solely to emphasize the complex and unpredictable nature of a successful introduction step. Mutagenesis is a highly stochastic event subject to the quantum-mechanic uncertainties associated with formation of infrequent tautomeric forms, or other alterations of nucleotides that contribute to misincorporation events [5, 26] . Although in RNA virus genetics it is often considered that mutation rates are high enough not to be the limiting factor for adaptability, there is a caveat in this argument when applied to a disease emergence that requires modification of the host range of a virus. In general, the generation of a specific mutant type will not be a limiting factor provided that: (i) the standard mutation rates that have been measured for RNA viruses operate [4, 14, 17] (discussed in the previous section), (ii) the population size of the replicating virus is sufficiently large, and (iii) that once the required mutation has occurred, the mutant virus maintains a sufficient fitness level, in the context of the surrounding mutant spectrum. However, a natural chance contact between an infected donor host and a potential recipient of another host species is unlikely to involve a large viral population size. Under such conditions, the occurrence of the mutations required for a change in host range may become a limiting factor for the introduction phase of disease emergence. In some designed experiments of adaptation of a virus in a new host species it has been shown than an initial inefficient replication in a recipient host is followed by fitness increase mediated by point mutations that occurred gradually in the mutant spectrum of the viral quasispecies evolving in vivo [64] . The barriers imposed by the host to a new viral pathogen may render establishment unlikely. The required viral genetic change must lie within the range achievable by mutation, recombination or reassortment (or their combinations) in the given environmental context.