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  • Review Article
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How retroviruses select their genomes

Nature Reviews Microbiology volume 3, pages 643–655 (2005)Cite this article

Key Points

  • All retroviruses — except spumaretroviruses — efficiently select and package two copies of their full-length RNA genomes as they assemble in infected cells.

  • The nucleocapsid (NC) domains of the assembling retroviral Gag polyproteins are primarily responsible for genome selection.

  • Upstream regions of the viral genomes, primarily located within 5′-untranslated regions (5′-UTRs), are essential for genome packaging and can independently direct the packaging of heterologous RNAs. In some cases, relatively small fragments of the UTRs can direct genome packaging, although not as efficiently as larger fragments or intact genomes.

  • Regions of retroviral genomes that promote genome packaging often overlap with segments that promote RNA dimerization, and there is mounting evidence that dimerization and packaging events are intimately coupled.

  • Except for the spumaretroviruses, all retroviral NC proteins contain one or two copies of a conserved zinc-knuckle motif that is crucial for packaging. The zinc knuckles generally contain a hydrophobic surface cleft, and in structurally characterized NC–RNA complexes the cleft serves as a binding site for exposed guanosine bases.

  • Structural studies of large portions of some retroviral UTRs, primarily using chemical and enzymatic protection experiments and phylogenetic analyses, indicate that RNA structural changes occur upon dimerization. It has been suggested that such changes may regulate translation and/or packaging.

  • High-resolution structural studies confirmed that fragments of the Moloney murine leukemia virus 5′-UTR undergo dimerization-dependent structural changes that regulate NC binding, consistent with the above proposal. It is currently unclear if other retroviruses, such as HIV, use similar mechanisms to selectively package a diploid genome.

  • Although good progress has been made over the past two decades to identify protein and RNA elements important for genome packaging, additional studies, possibly using combinations of high- and low-resolution technologies, are needed to determine how multiple elements interact to cooperatively promote genome packaging.

Abstract

As retroviruses assemble in infected cells, two copies of their full-length, unspliced RNA genomes are selected for packaging from a cellular milieu that contains a substantial excess of non-viral and spliced viral RNAs. Understanding the molecular details of genome packaging is important for the development of new antiviral strategies and to enhance the efficacy of retroviral vectors used in human gene therapy. Recent studies of viral RNA structure in vitro and in vivo and high-resolution studies of RNA fragments and protein–RNA complexes are helping to unravel the mechanism of genome packaging and providing the first glimpses of the initial stages of retrovirus assembly.

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Figure 1: General features of the orthoretroviral replication cycle.
Figure 2: Structure of the HIV-1 nucleocapsid protein.
Figure 3: RNA secondary structures for Moloney murine leukaemia virus genome packaging.
Figure 4: Structure of the Moloney murine leukaemia virus nucleocapsid protein bound to the core-encapsidation RNA element.
Figure 5: Proposed model for specific packaging of a dimeric genome.
Figure 6: Model for dimeric genome recognition and the early stage of retrovirus assembly.
Figure 7: RNA elements and protein–RNA complexes associated with HIV-1 genome packaging.

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  1. Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, 21250, Maryland, USA

    Victoria D'Souza & Michael F. Summers

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DATABASES

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avian leukosis virus

bovine leukaemia virus

feline immunodeficiency virus

HIV-1

HIV-2

Mason–Pfizer monkey virus

Moloney murine leukaemia virus

mouse mammary tumour virus

Rous sarcoma virus

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Glossary

GERM LINE

The cells that are in a direct mitotic line of descent from the zygote to its gametes, as distinct from somatic cells.

CONFORMER

One of many conformations that a protein or other molecule can adopt. For each molecule, the usual conformation that is adopted will be at energy minima.

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D'Souza, V., Summers, M. How retroviruses select their genomes. Nat Rev Microbiol 3, 643–655 (2005). https://doi.org/10.1038/nrmicro1210

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