The Evolutionary Pathway to Virulence of an RNA Virus

Abstract

Summary Paralytic polio once afflicted almost half a million children each year. The attenuated oral polio vaccine (OPV) has enabled world-wide vaccination efforts, which resulted in nearly complete control of the disease. However, poliovirus eradication is hampered globally by epidemics of vaccine-derived polio. Here, we describe a combined theoretical and experimental strategy that describes the molecular events leading from OPV to virulent strains. We discover that similar evolutionary events occur in most epidemics. The mutations and the evolutionary trajectories driving these epidemics are replicated using a simple cell-based experimental setup where the rate of evolution is intentionally accelerated. Furthermore, mutations accumulating during epidemics increase the replication fitness of the virus in cell culture and increase virulence in an animal model. Our study uncovers the evolutionary strategies by which vaccine strains become pathogenic, and provides a powerful framework for rational design of safer vaccine strains and for forecasting virulence of viruses.

Emergency Services of Viral RNAs: Repair and Remodeling

“…Nucleotide A 481 contributes to the attenuation phenotype of this vaccine virus, but it readily reverted to G in organisms of vaccinees, which is the event expected to disrupt the tertiary interaction. However, the potential for formation a stable C 398 -G 481 pair was regained in most isolates due to the reversion at position 398 as well (234,311,322) (Fig. 4B).…”

“…In addition, synonymous substitutions in the cis-acting RNA elements located within the protein-encoding sequences may also exhibit phenotypic effects (86,138,147,157,226). The possible involvement of some other mechanisms, such as the existence of alternative functional ORFs and the relevant frameshifting signals (78,(227)(228)(229)(230)(231) as well as the abundance of CpG and UpA dinucleotides (232)(233)(234)(235)(236), should also be taken into account.…”

Continued use of poliovirus after eradication: hyper‐attenuated strains as a safe alternative for release testing of human immunoglobulins

“…Almost full‐length PV genomes were amplified in duplicate by one‐step RT‐PCR using SuperScript® III One‐Step RT‐PCR System with Platinum® Taq High Fidelity DNA Polymerase (Invitrogen) and primers PCR F (5′‐ AGA GGC CCA CGT GGC GGC TAG ‐3′) and PVR 3′ (5’‐CCG AAT TAA AGA AAA ATT TAC CCC TAC A ‐3′. Primer PCR F was added after the reverse transcription step to eliminate non‐specific cDNA priming.…”

Evolutionary Virology at 40

“…They also risk establishing inaccurate general rules for RNA virus evolution if they are founded on the analysis of a limited number of case studies. For example, while poliovirus has been one of the mainstays of experimental approaches to studying viral evolution [for example, Vignuzzi et al (2006) and Stern et al (2017)] and has provided a wealth of valuable biological data (Regoes et al 2005), the evolution of poliovirus in the laboratory may not always reflect that in nature and it is mistaken to think that it is representative of all viruses. RNA viruses vary widely, having markedly different genome structures and replication cycles, infecting different hosts, possessing different propensities for disease, and experiencing variable rates of mutation and recombination.…”

“…Phylogenetic analyses are also limited by the availability of samples to inform on evolutionary patterns and processes, and are strongly impacted by sampling biases. As a consequence, phylogenetic analysis may sometimes be better used as a means to generate hypotheses that can then be tested experimentally, such as guiding the detection of virulence determinants in oral vaccine strains of poliovirus (Stern et al 2017), rather than as a precision tool to reveal the history of actual evolutionary events.…”