- Open Access
The retroviral RNA dimer linkage: different structures may reflect different roles
© Greatorex; licensee BioMed Central Ltd. 2004
- Received: 10 August 2004
- Accepted: 18 August 2004
- Published: 18 August 2004
Retroviruses are unique among virus families in having dimeric genomes. The RNA sequences and structures that link the two RNA molecules vary, and these differences provide clues as to the role of this feature in the viral lifecycles. This review draws upon examples from different retroviral families. Differences and similarities in both secondary and tertiary structure are discussed. The implication of varying roles for the dimer linkage in related viruses is considered.
- Human Immunodeficiency Virus Type
- Internal Ribosomal Entry Site
- Rous Sarcoma Virus
- Palindromic Sequence
- Template Switching
With relatively few genes compared to many other virus families, the retroviridae have evolved over the millenia to maximise the functions of their RNA genome. The genome serves as a versatile template from which various proteins can be translated by the use of splicing and by translational flexibility using scanning, IRES and frameshifting. It is also an RNA molecule capable of interacting with itself, and cellular and viral proteins. By these means, from an RNA around 7 – 12 kilobases long, the retroviridae have evolved to infect a wide range of species and cell types.
A unique characteristic of retroviral genomes is the fact that they are dimeric. The reasons for this are as yet unclear, and are discussed below. In brief, it is thought that the diploid genome allows template switching during reverse transcription and may be linked to recombination in some viruses. It may also play a role in translation of proteins and packaging of the RNA.
Much of the work on the nature, structure(s), and role of the dimer linkage has been based on Human Immunodeficiency Virus Type 1, and this has been recently reviewed ( and Russell et al this issue ). Whether or not HIV-1 is a representative model for other retroviruses is open to debate. However, there have been important contributions from investigators studying other retroviruses. They have shown both similarities with the HIV-1 motifs, and also, importantly, differences. The fact that distinct RNA structures are used by different retroviruses to perform the same purpose, namely to link their two RNA molecules, tells us something very important. For these viruses, whatever organism or cell they are infecting it has been advantageous to evolve to do so with a double complement of genome in their virion particles. However, diploidy may be used to benefit the virus in a number of ways and for different viruses the priorities may vary. This review will attempt to draw on several examples from viruses other than HIV-1, whilst of necessity drawing comparisons with the latter.
Retroviruses were discovered at the beginning of the 20th century [3, 4]. The unique nature of their genome was first discovered in the 1960s [5, 6] but the actual dimeric genomes were elucidated, and visualised by electron microscopy, a decade later [7, 8]. Bender and colleagues extracted the RNA from several different retroviruses and examined it by electron microscopy under denaturing conditions. The RNA appeared to be joined at a discrete point, termed the dimer linkage site (DLS). Using bromodU to label the RNA at one end, they were able to show that the molecules were joined at their 5' ends [9, 10]. Under less stringent conditions the genomes can be demonstrated to interact along their lengths  and it is this that probably contributes to confusing reports on the exact location of the primary DLS in different viruses.
RNA dimerisation in the primate lentiviruses, predominantly HIV-1, has subsequently been extensively studied , yet little has been published on this process in the non-primate lentiviruses. Early studies of rapid harvest virions of the prototype lentivirus, Maedi Visna virus (MVV), identified viral RNA with a Svedberg coefficient of 35S immediately post-budding, which increased with time to 70S. It is possible that weakly interacting dimers formed during RNA encapsidation may have been denatured during purification, however these observations are supportive of a progression from monomeric to dimeric RNA associated with viral maturation .
Since 1990  it has been possible to study in vitro the RNA elements involved in the dimer linkage first observed by EM. It was shown that RNA transcripts comprising sequences from the 5' end of the viral genome would migrate as two species of RNA when subjected to electrophoresis. By this means many subsequent studies were able to focus on isolating the elements and structures involved in dimerisation, and to investigate the role of the viral structural proteins in this process.
As yet investigators have not been able to agree on a distinct role for the dimer linkage. The fact that it is conserved amongst the retroviridae does not guarantee that its role will be the same in all retroviral families. The following section of the review will endeavour to explore some of the proposed roles, and examine the evidence from different retroviruses.
One of the key differences between HIV-1 and HIV-2 replication is their modes of packaging . Whilst the Gag protein of the former captures the genomic RNA in trans, the latter uses predominantly a cis mechanism. One might postulate therefore, that, if retroviruses must package a dimeric genome, it is critical in the case of HIV-2 that the genome is dimeric before interacting with the Gag polyprotein. Hence, the effect of mutations in the DM region may be to render the RNA monomeric and thus to severely impair packaging.
It is attractive to speculate that the reason packaging itself is not affected by DIS mutations to the same degree in HIV-1  is this difference in protein:RNA interaction. If the RNAs can interact at points other than the principal DIS over time, then perhaps the trans mechanism is less dependent on a high affinity dimer linkage?
The retroviral RNA genome structure does not stay static during the course of transcription, translation and ultimately packaging. Various investigators have suggested that this constantly changing RNA structure plays an intimate role in the viral replication [58–61]. It seems possible that linkage of the two RNA molecules constituting the genome is integral to the changes in RNA structure. As described in the article above, the dimer also acts as a mechanism for promoting recombination; may be a signal for packaging to occur; may be an inhibitory signal; may direct processes to occur in specific cellular compartments; and lastly, may be capable of interacting with cellular proteins.
In vivo data has revealed just how important an intact dimmer linkage may be to a retrovirus. For instance, there are intriguing differences in the effect of dimer mutations on viral infectivity depending on the cell type being infected . What the significance of this might be in the context of a viral infection is, as yet, unclear. The importance of the dimer linkage is perhaps most clearly exemplified by the observation that a patient infected with a viral isolate having a defective DLS, had a low viral load. The subsequent switch in the predominant virus to that with a competent DLS coincided with a rise in viral load . One can speculate that, at least in the case of HIV-1, only those viruses with a whole, optimised dimer linkage are capable of efficient infectivity. For the purposes of examining the role of retroviral RNA dimer sequences in the context of animal models, the non-human retroviruses, including the non-primate lentiviruses will be of great importance.
To sum up, retroviral dimeric genomes are linked by a variety of RNA structures, including kissing hairpins, GACG tetraloops and unusual CAG-tri loops. The differences in these interactions, and when or where they occur, may reflect different demands upon this unique feature, and highlight the elasticity of the RNA genome.
Many thanks to Andrew Lever for advice on, and editing of the manuscript. Particular thanks also go to Tom Monie for Figure 4, allowing description of unpublished work, and critical reading of the manuscript. In addition, thanks to Martin Zaccharias and Jose Gallego for contributions to the other figures, Paul Digard and Ian Brierley for critique.
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