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Genome-wide analysis of retroviral DNA integration

Nature Reviews Microbiology volume 3, pages 848–858 (2005)Cite this article

Key Points

  • In the past few years, with the availability of near-complete sequences for several vertebrate genomes, the targeting of retroviral DNA integration has been subjected to genomic analysis. These studies have shown that different retroviruses have different integration target-site preferences.

  • HIV favours integration in transcription units, particularly into active transcription units. In line with this, HIV integration is disfavoured in human endogenous retrovirus (HERV) elements, which are depleted in gene-rich regions of the genome and, in some studies, HIV integration is favoured in Alu elements, which are abundant in gene-rich chromosomal domains.

  • Murine leukaemia virus (MLV) favours integration near the 5′ ends of genes.

  • By contrast, avian sarcoma-leukosis virus (ASLV) shows a near-random distribution of integration sites in the human genome, with only a weak favouring of integration in genes.

  • The chromosomal environment can influence expression of integrated sequences — for example, integration of HIV into highly expressed cellular genes inhibits HIV transcription. These factors provide explanations for transcriptional latency in cells from HIV-infected patients.

  • Several chromosomal and nuclear factors might influence the targeting of retroviral integration. These include the presence of cellular proteins that can tether the integration complex to sites in the host genome, the intranuclear position of chromosomes, the accessibility of chromatin, and the cell-cycle status of the target cell.

  • Insertional activation of oncogenes by retroviral integration during human gene therapy has now been seen in three cases, which highlights the need for a further understanding of the mechanisms that direct retroviral integration.

Abstract

Retroviral vectors are often used to introduce therapeutic sequences into patients' cells. In recent years, gene therapy with retroviral vectors has had impressive therapeutic successes, but has also resulted in three cases of leukaemia caused by insertional mutagenesis, which has focused attention on the molecular determinants of retroviral-integration target-site selection. Here, we review retroviral DNA integration, with emphasis on recent genome-wide studies of targeting and on the status of efforts to modulate target-site selection.

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Figure 1: The DNA breaking and joining reactions that mediate integration.
Figure 2: Sites of integration of HIV or HIV-based vectors in the human genome.
Figure 3: Three human genes that have hosted multiple HIV integration events.
Figure 4: Candidate mechanisms that direct integration-site selection by retroviruses.

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Acknowledgements

This work was supported by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Microbiology, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, 19104-6076, Pennsylvania, USA

    Frederic Bushman, Mary Lewinski, Angela Ciuffi, Stephen Barr, Jeremy Leipzig, Sridhar Hannenhalli & Christian Hoffmann

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DATABASES

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Glossary

DNase I HYPERSENSITIVE SITES

DNA sites in chromosomes that show increased sensitivity to digestion by DNase I. These sites probably represent regions of the chromosome that are nucleosome-free, and often correspond to gene-control regions.

CPG ISLANDS

Regions in chromosomes that are enriched in the rare CpG dinucleotide. They often correspond to gene-control regions.

HUMAN ENDOGENOUS RETROVIRUSES

(HERVs). Sequences in human DNA that are derived from infection of the human germ line by retroviruses. They account for about 8% of the human genome sequence.

LONG INTERSPERSED NUCLEAR ELEMENTS

(LINEs). Non-long-terminal-repeat retrotransposons. These comprise the only known type of active transposon in the human genome.

ALU ELEMENTS

Repeated DNA sequences that contain recognition sites for the Alu restriction enzyme.

CENTROMERIC HETEROCHROMATIN

The distinctive type of protein–DNA complexes that are found at centromeres.

GIEMSA-LIGHT BANDING

Staining of the human chromosomes by the Giemsa procedure results in a pattern of light and dark bands, which roughly corresponds with the relative GC content and gene density.

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Bushman, F., Lewinski, M., Ciuffi, A. et al. Genome-wide analysis of retroviral DNA integration. Nat Rev Microbiol 3, 848–858 (2005). https://doi.org/10.1038/nrmicro1263

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