E Domingo

..Viruses occupy only a tiny portion of their potential sequence space. Such limited tolerance to mutations may open new avenues for combating viral infections...

..The results suggest that within a serotype of FMDV, antigenically highly divergent viruses can arise in the field by very limited sequence variation at exposed key residues of each of several antigenic sites...

..The results implicate the extreme heterogeneity of foot-and-mouth disease virus as an important element of viral pathogenesis...

..This indicates that a minimum genetic change can result in a highly amplified phenotypic effect, as regards the antigenicity of FMDV...

..However, the screening of isolates from six decades suggests that the virus, even within the confines of a single serotype, has exploited a minimum of its potential for antigenic variation...

..These critical replacements may yield viruses whose stability allows them to replicate efficiently and to expand the sequence repertoire of an antigenic site...

..These results indicate at least three different mechanisms for cell recognition by FMDV and suggest a potential for this virus to use multiple, alternative receptors for entry even into the same cell type...

..We review recent evidence to support this proposal, and we suggest that similar concepts may apply to other RNA viruses as well...

..The results suggest that strategies to combine reductions of viral load and viral fitness could be effectively associated with extinction mutagenesis as a potential new antiviral strategy...

..These results prove that infection of partially permissive cells can promote the rapid selection of virus variants that show alterations in cell tropism and are highly virulent for the same cells...

..Thus, the antigenic variation attained by FMDV type C over 6 decades was due to fluctuations among limited combinations of amino acid residues without net accumulation of amino acid replacements over time...

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..The molecular memory of the viral quasispecies influenced both the nature and the intensity of the response of the virus to a selective constraint...

..In addition, the results encourage the use of extended panels of well-characterized MAbs for a precise molecular analysis of the antigenic variation of FMDV, and of other viruses, in the field...

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..We suggest that persistent, inapparent infections of ruminants, in addition to being a reservoir of virus, may promote the rapid selection of antigenically variant FMDVs...

..It is concluded that variation of epitopes involved in neutralization of FMDV is extensive among subtypes of serotype C and also among individual isolates of one subtype...

..Essential residues at one stage of virus evolution may become dispensable at another not very distant point in the evolutionary landscape. Implications for FMDV evolution and vaccine design are discussed...

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..The non-additive effects of multiple replacements may modulate the extent of antigenic diversification of highly variable RNA viruses, and keep viruses confined within antigenic groups by precluding linear antigenic divergence...

..The results suggest that coevolution of BHK-21 cells and FMDV contributes to the maintenance of persistence in cell culture...

..Thus, the major antigenic site of FMDV shows heterogeneous dominance in a natural host. Possible implications for evolution of viral quasispecies are discussed...

..The results validate site-directed mutagenesis of constructs encoding capsid precursors as an approach to probe the structure of viral discontinuous epitopes not amenable to analysis with synthetic peptides...

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..Finally the quasi-species concept provides the basis for defining the selective factors that could influence the evolution of RNA virus and promote the emergence or reemergence of viral diseases...

..This is the first description of naturally occurring, defective particles of FMDV...

..The possibility of producing viable viruses lacking antigenic site A may find application in the design of new anti-FMD vaccines...

..The results support the proposal that, in spite of their involvement in antibody recognition, RGD and other FMDV loop residues are remarkably conserved because of their essential role in cell recognition...

..The results show that a single point mutation in an IRES element of a picornavirus can cause an increase in translation efficiency...

..Implications for FMDV evolution are discussed...

..The results underline the observation that greater insight into evolutionary processes of viruses may be gained from detailed clonal analyses of the mutant swarms at the sequence level...

..Therefore, different viral mutants from quasispecies replicating in vivo may be selected depending on the number of variant viruses relative to the number of susceptible cells...

..The possible relevance of this mechanism to viral persistence in vivo is discussed...

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..A model based on the selection of virus-resistant cell variants during persistence is proposed to interpret these observations. Implications about the persistence of viruses in their host cells and organisms are discussed...

..Thus, variability of highly conserved motifs, even those that viruses have adapted from functional cellular motifs, can contribute to phenotypic flexibility of RNA viruses in nature...

..The results suggest that combinations of mutagenic agents and antiviral inhibitors can effectively drive high-fitness virus into extinction...

..Implications for the evolution of RNA viruses are discussed...

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..A capacity to exploit alternative entry pathways may reflect the ancient evolutionary origins of viruses and a possible role as agents of horizontal gene transfers among cells...

..The results show that cells with a low level of expression of the aphthoviral 3C can be stably maintained and can provide a useful tool to study polyprotein processing...

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..The results document that an RNA virus can find multiple pathways to reach alternative high fitness peaks on the fitness landscape...

..In addition to documenting profound antigenic variation without immune selection, the results suggest that the repertoire of antigenic variants evolving in viral quasispecies may be greatly influenced by the population size of the virus...

..The results provide an account of the molecular basis of Muller's ratchet for an RNA virus, and insight into the types of genetic variants which populate the mutant spectra of FMDV quasispecies...

..It is proposed that the degree of tolerance to acceptance of amino acid replacements may modulate the variation at different antigenic epitopes of the same virus...

..Future trends in multiple target antiviral therapy and new approaches based on virus entry into error catastrophe (extinction mutagenesis) are discussed...

..Recent results suggest links between nutritional deficiencies and the generation of variant viruses, a possibility that is addressed in the present article...

..Also, mutant spectra are the target on which selection and random drift act to shape the long-term evolution of viruses. The biological relevance of mutant spectra is the central topic of this chapter...

..In striking similarity with the proposals for such early replicons, present-day RNA viruses consist of complex distributions of nonidentical but closely related genomes termed quasispecies...

..The results suggest, instead, that the behaviour of C1-BHK-Rc1 cultures is the result of complex interactions acting at the population level. Implications for viral persistence are discussed...

..New information has been recently obtained on the two sides of the survival line: the edge of adaptation and the edge of extinction...

..Such a comparison is contributing to the development of new antiviral strategies based on the transition of viral replication into error catastrophe...

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