Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity

Nature volume 441, pages 641–645 (2006)Cite this article

Abstract

Primate lentiviruses such as human immunodeficiency type 1 (HIV-1) have the capacity to infect non-dividing cells such as tissue macrophages1. In the process, viral complementary DNA traverses the nuclear envelope to integrate within chromatin2. Given the intimate association between chromatin and the nuclear envelope3, we examined whether HIV-1 appropriates nuclear envelope components during infection. Here we show that emerin, an integral inner-nuclear-envelope protein, is necessary for HIV-1 infection. Infection of primary macrophages lacking emerin was abortive in that viral cDNA localized to the nucleus but integration into chromatin was inefficient, and conversion of viral cDNA to non-functional episomal cDNA increased. HIV-1 cDNA associated with emerin in vivo, and the interaction of viral cDNA with chromatin was dependent on emerin. Barrier-to-autointegration factor (BAF), the LEM (LAP, emerin, MAN) binding partner of emerin, was required for the association of viral cDNA with emerin and for the ability of emerin to support virus infection. Therefore emerin, which bridges the interface between the inner nuclear envelope and chromatin, may be necessary for chromatin engagement by viral cDNA before integration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: siRNA-mediated silencing of nuclear envelope proteins inhibits HIV-1 infection of primary macrophages.
Figure 2: Emerin and BAF silencing promotes abortive infection of macrophages by preventing viral cDNA integration.
Figure 3: Association of HIV-1 cDNA with chromatin requires BAF and emerin.
Figure 4: HIV-1 cDNA association with emerin in vivo is dependent on BAF and requires the viral integrase.

Similar content being viewed by others

References

  1. Stevenson, M. HIV-1 pathogenesis. Nature Med. 9, 853–860 (2003)

    Article  CAS  Google Scholar 

  2. Greene, W. C. & Peterlin, B. M. Charting HIV's remarkable voyage through the cell: Basic science as a passport to future therapy. Nature Med. 8, 673–680 (2002)

    Article  CAS  Google Scholar 

  3. Gruenbaum, Y., Margalit, A., Goldman, R. D., Shumaker, D. K. & Wilson, K. L. The nuclear lamina comes of age. Nature Rev. Mol. Cell Biol. 6, 21–31 (2005)

    Article  CAS  Google Scholar 

  4. Zastrow, M. S., Vlcek, S. & Wilson, K. L. Proteins that bind A-type lamins: Integrating isolated clues. J. Cell Sci. 117, 979–987 (2004)

    Article  CAS  Google Scholar 

  5. Song, E. et al. Sustained small interfering RNA-mediated human immunodeficiency virus type 1 inhibition in primary macrophages. J. Virol. 77, 7174–7181 (2003)

    Article  CAS  Google Scholar 

  6. Zielske, S. P. & Stevenson, M. Importin 7 may be dispensable for human immunodeficiency virus type 1 and simian immunodeficiency virus infection of primary macrophages. J. Virol. 79, 11541–11546 (2005)

    Article  CAS  Google Scholar 

  7. Farnet, C. M. & Bushman, F. D. HIV-1 cDNA integration: requirement of HMG I(Y) protein for function of preintegration complexes in vitro. Cell 88, 483–492 (1997)

    Article  CAS  Google Scholar 

  8. Li, L. et al. Retroviral cDNA integration: stimulation by HMG I family proteins. J. Virol. 74, 10965–10974 (2000)

    Article  CAS  Google Scholar 

  9. Beitzel, B. & Bushman, F. Construction and analysis of cells lacking the HMGA gene family. Nucleic Acids Res. 31, 5025–5032 (2003)

    Article  CAS  Google Scholar 

  10. Lewis, P. F. & Emerman, M. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus. J. Virol. 68, 510–516 (1994)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Suzuki, Y., Yang, H. & Craigie, R. LAP2α and BAF collaborate to organize the Moloney murine leukemia virus preintegration complex. EMBO J. 23, 4670–4678 (2004)

    Article  CAS  Google Scholar 

  12. Swingler, S. et al. HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nature Med. 5, 997–1003 (1999)

    Article  CAS  Google Scholar 

  13. Mansharamani, M. et al. Barrier-to-autointegration factor BAF binds p55 Gag and matrix and is a host component of human immunodeficiency virus type 1 virions. J. Virol. 77, 13084–13092 (2003)

    Article  CAS  Google Scholar 

  14. Lee, M. S. & Craigie, R. A previously unidentified host protein protects retroviral DNA from autointegration. Proc. Natl Acad. Sci. USA 95, 1528–1533 (1998)

    Article  ADS  CAS  Google Scholar 

  15. Segura-Totten, M. & Wilson, K. L. BAF: roles in chromatin, nuclear structure and retrovirus integration. Trends Cell Biol. 14, 261–266 (2004)

    Article  CAS  Google Scholar 

  16. Miccoli, L. et al. Selective interactions of human kin17 and RPA proteins with chromatin and the nuclear matrix in a DNA damage- and cell cycle-regulated manner. Nucleic Acids Res. 31, 4162–4175 (2003)

    Article  CAS  Google Scholar 

  17. Lu, R. et al. Class II integrase mutants with changes in putative nuclear localization signals are primarily blocked at a postnuclear entry step of human immunodeficiency virus type 1 replication. J. Virol. 78, 12735–12746 (2004)

    Article  CAS  Google Scholar 

  18. Lau, A., Kanaar, R., Jackson, S. P. & O'Connor, M. J. Suppression of retroviral infection by the RAD52 DNA repair protein. EMBO J. 23, 3421–3429 (2004)

    Article  CAS  Google Scholar 

  19. Lin, C. W. & Engelman, A. The barrier-to-autointegration factor is a component of functional human immunodeficiency virus type 1 preintegration complexes. J. Virol. 77, 5030–5036 (2003)

    Article  CAS  Google Scholar 

  20. Stevenson, M. et al. Integration is not necessary for expression of human immunodeficiency virus type 1 protein products. J. Virol. 64, 2421–2425 (1990)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cherepanov, P., Ambrosio, A. L., Rahman, S., Ellenberger, T. & Engelman, A. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Natl Acad. Sci. USA 102, 17308–17313 (2005)

    Article  ADS  CAS  Google Scholar 

  22. Segura-Totten, M., Kowalski, A. K., Craigie, R. & Wilson, K. L. Barrier-to-autointegration factor: Major roles in chromatin decondensation and nuclear assembly. J. Cell Biol. 158, 475–485 (2002)

    Article  CAS  Google Scholar 

  23. Lee, K. K. et al. Distinct functional domains in emerin bind lamin A and DNA-bridging protein BAF. J. Cell Sci. 114, 4567–4573 (2001)

    CAS  PubMed  Google Scholar 

  24. Wiskerchen, M. & Muesing, M. A. Human immunodeficiency virus type 1 interase: Effects of mutations on viral ability to integrate, direct viral gene expression from unintegrated viral DNA templates, and sustain viral propagation in primary cells. J. Virol. 69, 376–386 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hazuda, D. J. et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287, 646–650 (2000)

    Article  ADS  CAS  Google Scholar 

  26. Emery, A. E. The muscular dystrophies. Lancet 359, 687–695 (2002)

    Article  CAS  Google Scholar 

  27. Jacque, J.-M., Triques, K. & Stevenson, M. Modulation of HIV-1 replication by RNAi. Nature 418, 435–438 (2002)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Dauphin and J. Zhou for research support, B. Mellor for preparation of the figures, K. Departie and L. Smith for manuscript preparation, and A. Engelman for providing HIV-1 integrase mutants. The University of Massachusetts Center for AIDS Research and the AIDS Research Reference Reagent Program, Division of AIDS, NIAID, National Institutes of Health (NIH), provided assay support and reagents. This study was supported by grants from the NIH to M.S.

Author information

Author notes

  1. Jean-Marc Jacque

    Present address: Centre for Research in Infectious Diseases, University College Dublin, Belfield, Dublin, 4, Ireland

Authors and Affiliations

  1. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Suite 319, Massachusetts, 01605, Worcester, USA

    Jean-Marc Jacque & Mario Stevenson

Authors
  1. Jean-Marc Jacque
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mario Stevenson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mario Stevenson.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1 and 2. (PDF 264 kb)

Supplementary Methods

This file contains additional information on the methods used in this study, including Cells and siRNA transfections, PCR analysis and Western blotting. This file also contains additional references. (DOC 54 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jacque, JM., Stevenson, M. The inner-nuclear-envelope protein emerin regulates HIV-1 infectivity. Nature 441, 641–645 (2006). https://doi.org/10.1038/nature04682

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04682

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing