L protein, the RNA-dependent RNA polymerase of hantaviruses

Kukkonen, Sami; Vaheri, Antti; Plyusnin, Alexander

doi:10.1007/s00705-004-0414-8

Cited by 48 publications

(54 citation statements)

References 123 publications

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“…The mutation frequency in the PUUV L segment is higher than in the S and M segments (44). None of the mutations observed in this study are in the proposed functional domains of RdRp (27), and it remains to be shown whether these mutations in any way alter the enzymatic, or any other, function of RdRp.…”

Section: Discussionmentioning

confidence: 56%

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Characterization of Two Substrains of Puumala Virus That Show Phenotypes That Are Different from Each Other and from the Original Strain

Sundström

Stoltz

Lagerqvist

et al. 2011

J Virol

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Hantaviruses, the causative agents of two emerging diseases, are negative-stranded RNA viruses with a tripartite genome. We isolated two substrains from a parental strain of Puumala hantavirus (PUUV-Pa), PUUV-small (PUUV-Sm) and PUUV-large (PUUV-La), named after their focus size when titrated. The two isolates were sequenced; this revealed differences at two positions in the nucleocapsid protein and two positions in the RNA-dependent RNA polymerase, but the glycoproteins were identical. We also detected a 43-nucleotide deletion in the PUUV-La S-segment 5 noncoding region covering a predicted hairpin loop structure that was found to be conserved among all hantaviruses with members of the rodent subfamily Arvicolinae as their hosts. Stocks of PUUV-La showed a lower ratio of viral RNA to infectious particles than stocks of PUUV-Sm and PUUV-Pa, indicating that PUUV-La replicated more efficiently in alpha/beta interferon (IFN-␣/␤)-defective Vero E6 cells. In Vero E6 cells, PUUV-La replicated to higher titers and PUUV-Sm replicated to lower titers than PUUV-Pa. In contrast, in IFN-competent MRC-5 cells, PUUV-La and PUUV-Sm replicated to similar levels, while PUUV-Pa progeny virus production was strongly inhibited. The different isolates clearly differed in their potential to induce innate immune responses in MRC-5 cells. PUUV-Pa caused stronger induction of IFN-␤, ISG56, and MxA than PUUV-La and PUUV-Sm, while PUUV-Sm caused stronger MxA and ISG56 induction than PUUV-La. These data demonstrate that the phenotypes of isolated hantavirus substrains can have substantial differences compared to each other and to the parental strain. Importantly, this implies that the reported differences in phenotypes for hantaviruses might depend more on chance due to spontaneous mutations during passage than inherited true differences between hantaviruses.

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Section: Discussionmentioning

confidence: 56%

“…It remains to be shown whether the mutations observed in N protein and RdRp are connected to each other or not. Hantavirus RdRp is a large protein of approximately 250 kDa (26,27). Whether hantavirus RdRp has functions other than transcriptase and replicase activity is currently not known.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Two Substrains of Puumala Virus That Show Phenotypes That Are Different from Each Other and from the Original Strain

Sundström

Stoltz

Lagerqvist

et al. 2011

J Virol

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“…This prediction is supported by data from sex chromosomes (Berlin and Ellegren 2006;Wykoff et al 2002), mitochondrial genomes (Nachman et al 1994(Nachman et al , 1996Rand and Kann 1996) and Drosophila genomic regions with different recombination rates (Haddrill et al 2007). There is evidence of homologous recombination in DNA viruses (Thiry et al 2004;Wilkinson and Weller 2003) and in both positive strand (Agol 2006;Lukashev 2005;Twiddy and Holmes 2003;Worobey and Holmes 1999) and negative-strand (Hughes 2007;Kukkonen et al 2005;Spann et al 2003) ssRNA viruses. Nonetheless, it seems probable that, because of their compact genomes, RNA viruses have considerably higher rates of recombination per nucleotide site than those of many DNA viruses, particularly dsDNA viruses, whose genomes are much larger.…”

Section: Discussionmentioning

confidence: 99%

More effective purifying selection on RNA viruses than in DNA viruses

Hughes

2007

Gene

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Analysis of the pattern of nucleotide diversity in 222 independent viral sequence datasets showed the prevalence of purifying selection. In spite of the higher mutation rate of RNA viruses, our analyses revealed stronger evidence of the action of purifying selection in RNA viruses than in DNA viruses. The ratio of nonsynonymous to synonymous nucleotide diversity was significantly lower in RNA viruses than in DNA viruses, indicating that nonsynonymous mutations have been removed at a greater rate (relative to the mutation rate) in the former than in the latter. Moreover, statistics that measure the occurrence of rare polymorphisms revealed significantly a greater excess of rare nonsynonymous polymorphisms in RNA viruses than in DNA viruses but no difference with respect to synonymous polymorphisms. Since rare nonsynonymous polymorphisms are likely to be undergoing the effects of purifying selection acting to eliminate them, this result implies a stronger signature of ongoing purifying selection in RNA viruses than in DNA viruses. Across datasets from both DNA viruses and RNA viruses, we found a negatively allometric relationship between nonsynonymous and synonymous nucleotide diversity; in other words, nonsynonymous nucleotide diversity increased with synonymous nucleotide diversity at a less than linear rate. These findings are most easily explained by the occurrence of slightly deleterious mutations. The fact that the negative allometry was more pronounced in RNA viruses than in DNA viruses provided additional evidence that purifying selection is more effective in the former than in the latter.

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“…Similar to other segmented negative-strand RNA viruses, the hantavirus RdRp initiates transcription by a unique cap-snatching mechanism (17)(18)(19)(20)(21). Based on in slico analysis, the regions around amino acids 1 to 250 and 751 to 1290 have been proposed to constitute the capsnatching endonuclease domain and catalytic domain, respectively (22,23). The regions from amino acids 251 to 750 and 1291 to 2153 have not been assigned any function (Fig.…”

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confidence: 99%