Parallels among positive-strand RNA viruses, reverse-transcribing viruses and double-stranded RNA viruses

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.

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.

Figure 2. Schematic overview of retrovirus and bromovirus genomes.

a | Schematic of the genomic RNA of a simple retrovirus and encoded virion proteins Gag and Gag–Pol. b | Schematic of bromovirus genomic RNAs 1, 2 and 3 and encoded RNA-replication factors 1a and 2a^pol. CA, capsid; Env, envelope-protein gene; ER, endoplasmic reticulum; MA, matrix; NC, nucleocapsid; RE, RNA template recruiting element for genomic RNA replication; TLS, 3′ tRNA-like sequence, which contains the promoter for negative-strand RNA synthesis; tRNA, host tRNA primer for negative-strand cDNA synthesis; Ψ, RNA-packaging signal.

Figure 3. Electron micrographs of membrane rearrangements associated with nodavirus and bromovirus RNA replication.

a | Mitochondria in a flock-house-nodavirus-infected Drosophila cell, showing the typical 50–70-nm, light-bulb-shaped spherular invaginations of the outer mitochondrial membrane into the expanded lumen between the inner and outer membranes. Reproduced with permission from Ref. © (2001) American Society for Microbiology. b | Mitochondrion in a flock-house-nodavirus-infected Drosophila cell that has been sectioned perpendicular to the axis of the spherule necks, rather than parallel to these axes as in panel a. This view reveals a 'vesicle packet' appearance (B. Kopek and P.A., unpublished results). Note that invagination into the lumen of any closed membrane compartment such as the endoplasmic reticulum (ER) or mitochondrial envelope creates a spherule interior that remains connected to the cytoplasm, but that in the section shown in b, the spherule appears separated from the cytoplasm by two or more bounding membranes. c | Similar 50–70-nm spherular vesicles invaginated from the outer perinuclear ER membrane into the ER lumen, in a yeast cell expressing brome mosaic virus (BMV) replication factor 1a in the absence of other viral components. Indistinguishable spherules occur in cells expressing 1a and BMV 2a^pol in a 20/1 ratio and replicating BMV RNA3. Reproduced with permission from Ref. © (2002) Elsevier. d | Karmellae-like layering of the outer perinuclear ER membrane in cells expressing BMV 1a plus elevated levels of BMV 2a^pol, and replicating BMV RNA3. Note at top and bottom left that the ∼60-nm intermembrane space is contiguous with the cytoplasm. Reproduced with permission from Ref. © (2004) National Academy of Sciences, USA.

Figure 4. Parallels between structure, assembly and function of retrovirus capsids, dsRNA-virus capsids and (+)RNA-virus RNA-replication complexes.

Highly simplified schematics are shown in each case. a | Assembly of a retrovirus capsid includes the interaction of membrane-associated Gag and Gag–Pol. Gag-dependent genomic RNA encapsidation takes place through packaging signal Ψ, and this is followed by budding. To emphasize similarities with panels b and c, synthesis of negative-strand cDNA (dashed lines) is shown prior to budding, as occurs for foamy retroviruses. b | Assembly and function of a bromovirus RNA-replication complex at the outer endoplasmic-reticulum membrane includes interaction of membrane-associated 1a and 2a^pol. 1a-dependent genomic RNA encapsidation takes place through the recruitment element (RE) template recruitment signal. This is followed by synthesis and retention of negative-strand RNA (dashed black lines), and asymmetric synthesis and export of positive-strand progeny RNA (red lines), which for at least some positive-strand RNA ((+)RNA) viruses proceeds by a semi-conservative mechanism as shown. c | Assembly and function of the capsid core of a generalized double-stranded (ds)RNA virus includes encapsidation of genomic RNAs by a packaging signal (PS), synthesis and retention of negative-strand RNA (dashed black lines) and subsequent asymmetric synthesis and export of positive-strand progeny RNA (red lines). (+)RNA synthesis by dsRNA viruses can be either semi-conservative, as shown, or conservative^,.

Figure 5. Structure–function parallels between reovirus and bromovirus RNA-replication factors.

The schematics illustrate similarities between interaction and function of reovirus core shell-forming protein λ1, RNA-capping protein λ2 and RNA-dependent polymerase λ3, and the interactions and functions of the brome mosaic virus (BMV) 1a C-proximal NTPase/helicase domain (1aC), 1a N-proximal RNA-capping domain (1aN) and 2a^pol RNA-dependent RNA polymerase. The reovirus λ1–λ2–λ3 interactions shown in the schematic occur at each of the twelve 5-fold axes of the reovirus core.

Figure 6. Parallels and distinctions among the life cycles of reverse-transcribing viruses, (+)RNA viruses and dsRNA viruses.

All three classes of virus share a similar replication cycle for their genomic RNA (central cyclical steps) but derive their infectious virions from different intermediates in that cycle (radial arrows). See text for further details. (+)RNA, positive-strand RNA; dsRNA, double-stranded RNA.