Viral Evolution: Accordion Adaptations Go Viral

RESEARCH HIGHLIGHTS Nature Reviews Microbiology | AOP, published online 10 September 2012; doi:10.1038/nrmicro2883 therefore viral replication. Vaccinia Although a higher gene copy virus, a Poxviridae member, has two number can be beneficial in the short Macmillan antagonists for PKR known as K3L term, in the long term the increased and E3L, which differ in their ability genome size would probably incur a to target PKR variants in different host substantial fitness cost. It is perhaps species. However, as PKR is antago- not a surprise, therefore, that in nized by a wide range of viruses, the viruses passaged ten times, 3–12% of protein undergoes rapid evolution, the sequenced K3L genes contained raising the question of how vaccinia a mutation that resulted in a single virus and its two PKR antagonists can amino acid substitution (His47Arg) keep up despite the low viral mutation which had been identified in a previ- rate. To investigate this problem, Elde ous genetic screen for K3L mutants et al. made use of the fact that K3L is with enhanced activity against a poor antagonist of human PKR; by human PKR. Importantly, in those propagating a strain of vaccinia virus viral genomes that had only a single lacking E3L (ΔE3L) in HeLa cells, they copy of K3L after ten passages, the could place a strong selective pressure frequency of the His47Arg mutation on K3L to adapt. The authors found had increased to 47%, suggesting that the ΔE3L virus initially replicated that there was a strong selective much more slowly than wild-type pressure to ensure that the His47Arg virus in HeLa cells over 48 hours, but allele was maintained in viruses that after six passages the rate of rep- with reduced K3L copy numbers. VIRAL EVOLUTION lication increased tenfold, suggesting Finally, the authors investigated what that the virus had adapted. would happen to the K3L genomic To determine the basis of this expansions if the selective pressure Accordion adaptation, the authors deep- were reduced by propagating the sequenced the viral populations to ΔE3L virus in BHK cells (in which a adaptations go viral ~1,000‑fold genome coverage. Despite single copy of wild-type K3L is suf- finding only two non-synonymous ficient to overcome the PKR variant). Unlike RNA viruses, which couple mutations and one synonymous They observed that after just four high mutation rates with short genera- mutation that occurred at a frequency passages, all of the viral genomes tion times to adapt to host antiviral of more than 1%, they also found contained either a single K3L copy defences, double-stranded (ds) DNA a substantial spike in the sequence or considerably fewer copies than the viruses exhibit low mutation rates, coverage exclusively over the K3L ΔE3L viruses that were replicated in which raises the question of how they gene, indicative of an increase in its HeLa cells. stay abreast in the arms race between copy number in the viral genomes. Thus, gene expansion provides a virus and the host cell defences. Accordingly, using Southern blot- the mutational space in which Writing in Cell, Elde et al. now show ting, the authors observed a highly poxviruses can adapt to overcome that members of one family of large heterogeneous pool of viral genomes an antiviral factor, and this expan- dsDNA viruses, Poxviridae, use a that contained as many as 15 or more sion is followed by gene deletion gene ‘genomic accordion’ in which a viral copies of the K3L gene, with the copy and fixation of the adapted allele. expansion gene encoding an anti-host factor is number directly correlating to the Interestingly, a similar process has provides the amplified, thus buying the virus time increase in viral replication from previously been shown to occur mutational to gain an adaptive mutation. passage to passage. Importantly, the during the appearance of bacterial One of the key ways in which host adapted viruses produced higher resistance to antibiotics, suggesting space in which cells defend themselves against invad- levels of K3L than the parental ΔE3L that such genomic accordions might poxviruses ing viruses is through protein kinase R virus, and knockdown of K3L expres- be a widespread and fundamental can adapt to (PKR; also known as eIF2αK2), which sion using small interfering RNAs mechanism to facilitate adaptation. is activated following detection of viral reduced viral replication levels back Andrew Jermy overcome an dsRNA and leads to the phosphoryla- to those of the ΔE3L parent, indicat- ORIGINAL RESEARCH PAPER Elde, N. C. et al. antiviral factor tion of eukaryotic translation initia- ing that increased K3L copy number Poxviruses deploy genomic accordions to adapt tion factor 2α (eIF2α), resulting in the was necessary and sufficient for the rapidly against host antiviral defences. Cell 150, 831–841 (2012) inhibition of protein synthesis and increased viral replication. NATURE REVIEWS | MICROBIOLOGY VOLUME 10 | OCTOBER 2012 © 2012 Macmillan Publishers Limited. All rights reserved.

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