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Viruses at the Edge of Adaptation

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Viruses at the Edge of Adaptation Virology 270, 251–253 (2000) doi:10.1006/viro.2000.0320, available online at http://www.idealibrary.com on MINIREVIEW Viruses at the Edge of Adaptation Esteban Domingo1 Centro de Biologı´a Molecular “Severo Ochoa,” (CSIC-UAM) Universidad Auto´noma de Madrid, Cantoblanco, 28049 Madrid, Spain Received February 25, 2000; accepted March 14, 2000 How vulnerable is the line that separates adaptation from extinction? Viruses, in particular RNA viruses, are well known for their high rates of genetic variation and their potential to adapt to environmental modifications (Drake and Holland, 1999; Domingo et al., 2000). Yet, fitness variations—both increases and decreases—can be spectacularly rapid, and the simple genetic stratagem of forcing virus multiplication to go through repeated genetic bottlenecks can induce fitness losses, at times near viral extinction. New information has been recently obtained on the two sides of the survival line: the edge of adaptation and the edge of extinction. © 2000 Academic Press SUBTLE ADAPTIVE STRATEGIES present in the population. Furthermore, this particular variant was systematically selected, while, when absent RNA virus quasispecies are highly effective in the from memory, its selection was rare (Ruiz-Jarabo et al., exploration of new genomic sequences (Eigen and 2000). In agreement with the concept that memory ge- Biebricher, 1988). It has long been known that mutant nomes are part of the mutant spectrum of the quasispe- swarms (the mutant spectra that populate viral quasispe- cies, memory was erased when the populations were cies) contain potentially useful variants [those with in- subjected to genetic bottlenecks (Fig. 1). Because of the creased resistance to antiviral agents, altered interferon- existence of a molecular memory, a viral quasispecies inducing capacity, or antibody-escape and cytotoxic T may be capable of reacting swiftly to a selective con- lymphocyte (CTL)-escape mutants, among others]. A straint which has been already experienced by the same new feature of quasispecies dynamics which may turn virus population. Immune and other internal physiologi- out to be important for viral adaptation has been re- cal responses in infected hosts are hardly uniform and vealed: the presence of a memory of past evolutionary continuous; the same must apply to concentrations of history, imprinted on minority components of the mutant antiviral inhibitors when they reach the target replication spectrum (Ruiz-Jarabo et al., 2000). The experiments took sites of viruses. Memory—a feature of biological, com- advantage of a number of well-characterized mutants of plex adaptive systems (such as the immune system)—is the important animal pathogen foot-and-mouth disease likely to represent an advantage for the virus whenever virus (FMDV). One of the memory markers was an un- fluctuating selective pressures occur. Are viruses which usual internal polyadenylate, known to be associated are endowed with such subtle adaptive strategies im- with fitness decrease of FMDV clones subjected to re- mune to extinction? A complementary line of research peated plaque-to-plaque transfers (Escarmı´s et al., 1996, suggests that, hopefully, they are not. 1999). When clones were allowed to recover fitness, genomes with additional adenylate residues were no THE PRICE OF MISTAKES longer detected in the consensus sequence, but were The maintenance of genetic information of any organ- maintained in the mutant spectrum after at least 225 ism requires a minimal fidelity level during copying of doublings of the amount of infectious particles. The template molecules in the process of genome replica- same was true of an antigenic variant of FMDV. Its tion. This applies to viruses (Eigen and Biebricher, 1988; presence in the quasispecies memory resulted in an Schuster and Stadler, 1999). Excess mutations—the so- increase in the frequency of antibody-escape mutants called violation of the error threshold—should abolish virus infectivity (Fig. 2). Experimental support for this concept was obtained initially for poliovirus, vesicular 1 To whom correspondence should be addressed. Fax: 34-91- stomatitis virus (Holland et al., 1990), and a retroviral 3974799. E-mail: [email protected]. vector (Pathak and Temin, 1992), all of which underwent 0042-6822/00 $35.00 251 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved. 252 MINIREVIEW FIG. 1. Schematic representation of memory in viral quasispecies. Viral quasispecies are represented by genome distributions (horizontal lines) with an average of about four mutations (symbols on lines) per genome. To illustrate memory, the mutant spectrum on the left is divided into three frequency levels: 1, the most frequent genomes; 2, minority components potentially occupied by memory genomes; and 3, basal minority components as a result of mutational pressure and competitive rating of mutants (Eigen and Biebricher, 1988; Schuster and Stadler, 1999; Domingo et al., 2000). Initially, a marker “A” (indicated on the genome) belongs to the basal minority components. When this marker is selected, it becomes dominant (middle distribution, with accompanying random mutations, since marker A belongs to a category of genomes, not to a single genome). When genomes with A show a selective disadvantage relative to competitors lacking A (for example, revertants), genomes with A eventually will not be detected in the consensus sequence after extensive replication. However, they may remain at level 2 as part of memory genomes of the mutant spectrum (upper right distribution). In the case of antigenic variants analyzed by Ruiz-Jarabo et al. (2000), the initial selection for A resulted in a number of alternative variants (with different antigenically relevant amino acid substitutions), each isolated with low frequency. In contrast, once a specific variant was incorporated into memory its selection became deterministic. When bottleneck passages intervene (small, filled arrow), memory is lost and genomes with A return to level 3 (lower right distribution). Different memory levels can be attained for different genetic markers, depending on fitness values and mutation rates (Ruiz-Jarabo et al., 2000), in what appears to be a highly dynamic process which is now under further investigation. drastic losses of infectivity when subjected to chemical enough so as to induce the irreversible transition into mutagenesis during their replication. Recently, additional error catastrophe (violation of the error threshold) of viral evidence has been obtained with HIV-1, in a series of replicons (Eigen and Biebricher, 1988; Schuster and Stad- elegant experiments employing mutagenic deoxynucleo- ler, 1999; Domingo et al., 2000). These may seem at side analogs (Loeb et al., 1999). These authors have present harsh demands. However, this new line of re- coined the term “lethal mutagenesis” to describe the search is of utmost importance in view of the continuing mutagen-induced loss of viral infectivity. Could increased difficulties in developing effective vaccines for many viral mutagenesis be turned into an effective antiviral strategy diseases, the limited success of current antiviral thera- (Loeb and Mullins, 2000)? At least two conditions should pies, and a strikingly sustained incidence of emerging be fulfilled: the mutagenic drug should target viral RNA- and reemerging viral diseases. dependent RNA or DNA polymerases, but not host en- Both the concept of memory and the strategy of lethal zymes. Also, drug concentrations should be effective mutagenesis have arisen as consequences of quasispe- MINIREVIEW 253 ACKNOWLEDGMENTS I am indebted to John J. Holland for many years of collaboration and to C. M. Ruı´z-Jarabo, S. Sierra, A. Arias, E. Baranowski, and C. Escarmı´s for important contributions to the FMDV research reviewed here. This work was supported by Grants PM97-0060-01, FIS 98/0054-01, and FAIR5PL97-3665 and Fundacio´n Ramo´n Areces. REFERENCES Domingo, E., Biebricher, C., Holland, J. J., and Eigen, M. (2000). “Qua- sispecies and RNA Virus Evolution: Principles and Consequences.” Landes Bioscience, Austin. Drake, J. W., and Holland, J. J. (1999). Mutation rates among RNA viruses. Proc. Natl. Acad. Sci. USA 96, 13910–13913. Eigen, M., and Biebricher, C. K. (1988). Sequence space and quasispe- cies distribution. In “RNA Genetics” (E. Domingo, P. Ahlquist, and J. J. Holland, Eds.), Vol. 3, pp. 211–245. CRC Press, Boca Raton. Escarmı´s, C., Da´vila, M., Charpentier, N., Bracho, A., Moya, A., and Domingo, E. (1996). Genetic lesions associated with Muller’s ratchet FIG. 2. Error catastrophe and lethal mutagenesis. One of the impli- in an RNA virus. J. Mol. Biol. 264, 255–267. cations of the quasispecies nature of RNA viruses is the existence of Escarmı´s, C., Da´vila, M., and Domingo, E. (1999). Multiple molecular an error threshold relationship, which links the maximum meaningful pathways for fitness recovery of an RNA virus debilitated by opera- genetic information with the superiority of the master (dominant) tion of Muller’s ratchet. J. Mol. Biol 285, 495–505. genomic sequence (over the mutant spectrum) and the copying fidelity Holland, J. J., Domingo, E., de la Torre, J. C., and Steinhauer, D. A. (1990). during replication (Eigen and Biebricher, 1988; Schuster and Stadler, Mutation frequencies at defined single codon sites in vesicular 1999; Domingo et al., 2000). In this simplified scheme, the error thresh- stomatitis virus and poliovirus can be increased only slightly by old (vertical line) marks
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