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Parallels Among Positive-Strand RNA Viruses, Reverse-Transcribing Viruses and Double-Stranded RNA Viruses

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Parallels Among Positive-Strand RNA Viruses, Reverse-Transcribing Viruses and Double-Stranded RNA Viruses REVIEWS Parallels among positive-strand RNA viruses, reverse-transcribing viruses and double-stranded RNA viruses Paul Ahlquist Abstract | Viruses are divided into seven classes on the basis of differing strategies for storing and replicating their genomes through RNA and/or DNA intermediates. Despite major differences among these classes, recent results reveal that the non-virion, intracellular RNA- replication complexes of some positive-strand RNA viruses share parallels with the structure, assembly and function of the replicative cores of extracellular virions of reverse-transcribing viruses and double-stranded RNA viruses. Therefore, at least four of seven principal virus classes share several underlying features in genome replication and might have emerged from common ancestors. This has implications for virus function, evolution and control. Positive-strand RNA virus Despite continuing advances, established and emerging ssRNA or dsRNA. Other viruses replicate by intercon- A virus, the infectious virions of viruses remain major causes of human disease, with verting their genomes between RNA and DNA. The viri- which contain the genome in a dramatic costs in mortality, morbidity and economic ons of such reverse-transcribing viruses always initially single-stranded, messenger- terms. In addition to acute diseases, viruses cause at package the RNA forms of their genomes, and either sense RNA form. least 15–20% of human cancers1,2 and are implicated in might (for example, hepadnaviruses and foamy retro- neurological and other chronic disorders. One of many viruses) or might not (for example, orthoretroviruses) challenges in controlling viruses and virus-mediated dis- reverse-transcribe the RNA into DNA before the virion eases is that viruses show an amazing diversity in basic exits the initially infected producer cell. characteristics and life cycles, including differences in Viruses in each of these seven classes tend to share virion structure, replication strategies, genetic organiza- additional features, such as gene-expression strategies tion, gene expression and many other fundamental proc- and so on, that further cluster and differentiate their esses. Therefore, even the very processes against which members from the other classes, showing that these antivirals are targeted often differ radically among virus classes represent meaningful, functionally distinct group- classes. Inherent in this remarkable variety are intrigu- ings and probable evolutionary lineages. Some of these ing issues about the multiplicity of virus origins and the variations arise because the type of nucleic acid delivered functional and evolutionary relations of existing viruses. by the virion to a target cell dictates early infection and Such issues have practical as well as academic impor- gene-expression steps. For example, to initiate viral gene tance, as underlying similarities among virus classes expression, dsRNA virus virions and negative-strand might serve as a foundation for broader-spectrum RNA ((–)RNA) virus virions contain viral polymerases antiviral strategies. that transcribe the genome into translatable mRNA, and One of the most elemental differences among viruses reverse-transcribing-virus virions contain polymerases is their diversity in genome replication and encapsidation that copy the genome into cell-transcribable DNA strategies, which define seven major classes (FIG. 1). Some (BOX 1). Positive-strand RNA ((+)RNA) viruses, the virions of viruses replicate their genomes solely through DNA inter- which deliver immediately translatable messenger-sense Institute for Molecular Virology and Howard Hughes mediates, packaging these genomes in infectious virions RNAs, encapsidate their RNA without a polymerase Medical Institute, University either as double-stranded (ds)DNA or single-stranded and form strictly intracellular RNA-replication and of Wisconsin–Madison, (ss)DNA. By contrast, most viruses replicate their mRNA transcription complexes (BOX 1). Madison, Wisconsin 53706, genomes solely through RNA intermediates. Such RNA Despite these and other differences, recent results USA. e-mail: [email protected] viruses are divided into three classes based on whether have revealed fundamental parallels in the genome- doi:10.1038/nrmicro1389 their virions package the genome as mRNA-sense replication processes of certain (+)RNA viruses, dsRNA Published online 3 April 2006 (positive-strand) ssRNA, antisense (negative-strand) viruses and reverse-transcribing viruses. In particular, the NATURE REVIEWS | MICROBIOLOGY VOLUME 4 | MAY 2006 | 371 © 2006 Nature Publishing Group REVIEWS RNA viruses Reverse-transcribing DNA viruses viruses Genome replication RNA RNA RNA DNA DNA DNA cycle Virion (–)RNA dsRNA (+)RNA (+)RNA dsDNA ssDNA dsDNA contents Examples Influenza viruses, Reoviruses, Hepatitis C virus, HIV, other Hepatitis B Parvo- Herpes- Ebola viruses rotaviruses SARS viruses retroviruses virus viruses viruses Figure 1 | Seven classes of virus distinguished by genome replication and encapsidation strategies. The bracket highlights the four virus classes emphasized in this review. (+)RNA, positive-strand RNA, which is single-stranded RNA of the same polarity as viral mRNA; (-)RNA, negative-strand RNA, which is single-stranded RNA of anti-mRNA polarity; dsRNA, double-stranded RNA; SARS, severe acute respiratory syndrome. intracellular RNA-replication complexes of some, if not retroviruses, a cellular tRNA covalently primes negative- many, (+)RNA viruses share several similarities with the strand cDNA synthesis, whereas for the relevant (+)RNA replicative cores of virions from both dsRNA viruses and viruses, a viral tRNA-like element serves as a recognition reverse-transcribing viruses. This review outlines these site and template for (–)RNA synthesis that is initiated similarities and their potential implications for virus de novo, without a primer. A natural intermediate and function and evolution. As primary examples, we review potential evolutionary link between these processes was similarities among (+)RNA viruses in the alphavirus-like identified by Lambowitz and colleagues, who showed that superfamily, the dsRNA reoviruses and the retroviruses. a Neurospora crassa mitochondrial retroplasmid initiates Other shared characteristics with similar evolutionary reverse transcription without a primer at the tRNA-like implications have been recognized recently among cer- 3′ end of its genomic RNA, paralleling negative-strand tain other (+)RNA viruses, the dsRNA birnaviruses and initiation by (+)RNA viruses14. the reverse-transcribing hepadnaviruses, including par- allels in viral RNA-polymerase structure, capsid proteins Membrane-associated RNA-replication complexes. As and protein priming of genome replication3–7. noted above, (+)RNA viruses differ from retroviruses Negative-strand RNA ((–)RNA) viruses (FIG. 1) also share and other RNA viruses in that they do not encapsidate similarities with some of the basic features reviewed their polymerases in extracellular virions. Nevertheless, here, suggesting that the functional and evolutionary emerging results show that similarities between (+)RNA- parallels discussed below might be extended further. virus RNA replication and retrovirus reverse tran- These possibilities are not discussed here in detail for scription are not limited to aspects of negative-strand reasons of space. In addition, whereas (+)RNA viruses, initiation and the general similarities of RNA and DNA dsRNA viruses and reverse-transcribing viruses each polymerases. Instead, as detailed below, (+)RNA-virus use identical (+)RNA molecules as genome-replication RNA replication occurs in virus-induced compartments intermediates and mRNAs, (–)RNA viruses are distin- which have many similarities to the replicative cores or guished by using different forms of (+)RNA for these capsids of retrovirus virions. functions. (+)RNA-virus replication is invariably localized to intracellular membranes. Different (+)RNA viruses tar- (+)RNA virus and retrovirus parallels get distinct but usually specific membranes, such as those tRNAs and genome replication. One of the first simi- of the endoplasmic reticulum (ER)15–19, endosomes20,21, larities recognized between the replication of retroviruses mitochondria22 or chloroplasts23. RNA replication is and (+)RNA viruses was the role of tRNAs in initiating usually associated with rearrangements of these target retroviral reverse transcription and of tRNA-like elements membranes, often giving rise to membrane invagina- in initiating RNA replication by a subset of (+)RNA tions, single- or double-membrane vesicles, membrane- viruses such as the bromoviruses8,9 (FIG. 2). Bromoviruses, bound vesicle packets and other structures. discussed further below, have three genomic RNAs with For many (+)RNA viruses, RNA synthesis localizes Negative-strand RNA virus highly conserved, structured, tRNA-like 3′ ends (FIG. 2b). to membranes bearing 50–70-nm vesicular compart- A virus, the infectious virions of These 3′ ends terminate in 3′-CCA sequences that ments that are invaginated away from the cytoplasm which contain the genome in a OH single-stranded, anti- are completed by tRNA-nucleotidyl transferase, they into the lumen of the affected secretory compartment messenger-sense RNA form. are specifically aminoacylated in vitro and in vivo with or organelle. Such invaginations, termed spherules, tyrosine, and they contain the promoter for (–)RNA were first visualized in early electron microscopy (EM) Retroplasmid synthesis10–13.
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