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Dimerization of retroviral RNA genomes: an inseparable pair

Nature Reviews Microbiology volume 2, pages 461–472 (2004)Cite this article

Key Points

  • Retroviruses are diploid and the two copies of the genome are non-covalently linked together. The main dimer linkage structure is located in the 5′ region of the genome.

  • In HIV-1, RNA dimerization is initiated by the base-pairing of a self-complementary sequence that is located in the loop of an RNA hairpin motif. This initial loose dimer is maturated into a more stable (tight) dimer.

  • In other retroviruses, initiation of RNA dimerization is more complicated and involves several sequences. In yeast retrotransposons, the tRNA species that is used as a reverse transcription primer participates in RNA dimerization in vitro.

  • In most retroviruses, RNA dimerization is a prerequisite for packaging of the genomic RNA. The HIV-1 dimerization initiation site identified in vitro is not the only sequence participating in RNA dimerization in vivo.

  • In cells, RNA dimerization is linked to trafficking of the Gag precursor protein and the RNA dimer can be used as a scaffold during viral assembly. Retroviral RNA dimers undergo conformational changes during virion maturation, but the structure of the in vivo matured dimer remains speculative.

  • RNA dimerization is crucial for reverse transcription and recombination. Drugs targeting RNA dimerization could potentially limit the emergence of multidrug-resistant viruses.

Abstract

Many viruses carry more than one segment of nucleic acid into the virion particle, but retroviruses are the only known group of viruses that contain two identical (or nearly identical) copies of the RNA genome within the virion. These RNA genomes are non-covalently joined together through a process known as genomic RNA dimerization. Uniquely, the RNA dimerization of the retroviral genome is of crucial importance for efficient retroviral replication. In this article, our current understanding of the relationship between retroviral genome conformation, dimerization and replication is reviewed.

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Figure 1: Schematic of the HIV-1 replication cycle.
Figure 2: The HIV-1 dimerization initiation site.
Figure 3: X-ray crystal structures of the kissing-loop complex and extended duplex of a 23-mer RNA (subtype A isolate).
Figure 4: Model showing the putative conformational switch that is proposed to regulate translation and packaging of the HIV-1 genomic RNA.

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Acknowledgements

J.-C.P. and R.M. thank B. Ehresmann and C. Ehresmann for their constant interest and support, and thank the former members of the Ehresmann laboratory for their contribution to the study of retroviral RNA dimerization. M.S.-X. and J.M. thank S. Campbell for her assistance in some of the graphic design, plus former and current members of the Burnet Institute for their support and contribution to the study of retroviral assembly. We thank all our reviewers for their insightful comments, and apologize to those colleagues whose research has not been highlighted owing to length constrains. The selected examples merely reflect our personal interest. This work was supported by the Agence Nationale de Recherches sur le SIDA in France, and the Australian National Health and Medical Research Council C. J. Martin Fellowship, Monash University and Pharmacia–Pfizer Foundation in Australia.

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  1. Jean-Christophe Paillart and Miranda Shehu-Xhilaga: J.-C.P. and M.S.-X. contributed equally to this work.

Authors and Affiliations

  1. UPR 9002 du CNRS affiliée à l'Université Louis Pasteur, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, 67084, Cedex, France

    Jean-Christophe Paillart & Roland Marquet

  2. Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, 3004, Victoria, Australia

    Miranda Shehu-Xhilaga & Johnson Mak

  3. Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800, Victoria, Australia

    Johnson Mak

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DATABASES

Entrez

HIV-1

HIV-2

SwissProt

Gag

FURTHER INFORMATION

Johnson Mak's laboratory

Roland Marquet's laboratory

Glossary

KISSING-LOOP COMPLEX

Formed when two RNA hairpins interact through their complementary loops.

EXTENDED DUPLEX

A complex that results from complete intermolecular base-pairing of two stem loops. It can be obtained from the kissing-loop complex by disrupting the intramolecular stems and forming intermolecular base-pairs.

IN VIVO MATURATION

A process that depends on the processing of the polyprotein Gag and results in increased thermal stability of the RNA dimer.

5′-UNTRANSLATED REGION

(5′-UTR). An RNA sequence that is found upstream of the protein-coding sequence.

RETROVIRAL RECOMBINATION

A process to generate new strains of retroviruses by mixing genetic materials of two different strains of parental retroviruses.

CRM1

(Chromosome region maintenance 1). A cellular protein that mediates the nuclear export of numerous proteins.

HAART

(Highly Active Antiretroviral Treatment). Consists of a minimum of three drugs that inhibit the activity of the viral enzymes reverse transcriptase or protease. The first compound of a third drug class, the fusion inhibitors, has recently been approved for treatment.

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Paillart, JC., Shehu-Xhilaga, M., Marquet, R. et al. Dimerization of retroviral RNA genomes: an inseparable pair. Nat Rev Microbiol 2, 461–472 (2004). https://doi.org/10.1038/nrmicro903

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