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.

Global landscape of HIV–human protein complexes

Nature volume 481, pages 365–370 (2012)Cite this article

Subjects

Abstract

Human immunodeficiency virus (HIV) has a small genome and therefore relies heavily on the host cellular machinery to replicate. Identifying which host proteins and complexes come into physical contact with the viral proteins is crucial for a comprehensive understanding of how HIV rewires the host’s cellular machinery during the course of infection. Here we report the use of affinity tagging and purification mass spectrometry1,2,3 to determine systematically the physical interactions of all 18 HIV-1 proteins and polyproteins with host proteins in two different human cell lines (HEK293 and Jurkat). Using a quantitative scoring system that we call MiST, we identified with high confidence 497 HIV–human protein–protein interactions involving 435 individual human proteins, with ∼40% of the interactions being identified in both cell types. We found that the host proteins hijacked by HIV, especially those found interacting in both cell types, are highly conserved across primates. We uncovered a number of host complexes targeted by viral proteins, including the finding that HIV protease cleaves eIF3d, a subunit of eukaryotic translation initiation factor 3. This host protein is one of eleven identified in this analysis that act to inhibit HIV replication. This data set facilitates a more comprehensive and detailed understanding of how the host machinery is manipulated during the course of HIV infection.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Affinity purification of HIV-1 proteins, analysis and scoring of mass spectrometry data.
Figure 2: Comparison of PPI data with other HIV data sets.
Figure 3: Network representation of the HIV–human PPIs.
Figure 4: eIF3d is cleaved by HIV-1 PR and inhibits infection.

References

  1. Gavin, A. C. et al. Proteome survey reveals modularity of the yeast cell machinery. Nature 440, 631–636 (2006)

    Article  ADS  CAS  Google Scholar 

  2. Jäger, S. et al. Purification and characterization of HIV-human protein complexes. Methods 53, 13–19 (2011)

    Article  Google Scholar 

  3. Krogan, N. J. et al. Global landscape of protein complexes in the yeast Saccharomyces cerevisiae . Nature 440, 637–643 (2006)

    Article  ADS  CAS  Google Scholar 

  4. Sowa, M. E., Bennett, E. J., Gygi, S. P. & Harper, J. W. Defining the human deubiquitinating enzyme interaction landscape. Cell 138, 389–403 (2009)

    Article  CAS  Google Scholar 

  5. Yu, H. et al. High-quality binary protein interaction map of the yeast interactome network. Science 322, 104–110 (2008)

    Article  ADS  CAS  Google Scholar 

  6. Stelzl, U. et al. A human protein-protein interaction network: a resource for annotating the proteome. Cell 122, 957–968 (2005)

    Article  CAS  Google Scholar 

  7. Tarassov, K. et al. An in vivo map of the yeast protein interactome. Science 320, 1465–1470 (2008)

    Article  ADS  CAS  Google Scholar 

  8. Calderwood, M. A. et al. Epstein-Barr virus and virus human protein interaction maps. Proc. Natl Acad. Sci. USA 104, 7606–7611 (2007)

    Article  ADS  CAS  Google Scholar 

  9. Shapira, S. D. et al. A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell 139, 1255–1267 (2009)

    Article  Google Scholar 

  10. Collins, S. R. et al. Toward a comprehensive atlas of the physical interactome of Saccharomyces cerevisiae . Mol. Cell. Proteomics 6, 439–450 (2007)

    Article  CAS  Google Scholar 

  11. Choi, H. et al. SAINT: probabilistic scoring of affinity purification-mass spectrometry data. Nature Methods 8, 70–73 (2011)

    Article  CAS  Google Scholar 

  12. Malim, M. H. & Emerman, M. HIV-1 accessory proteins–ensuring viral survival in a hostile environment. Cell Host Microbe 3, 388–398 (2008)

    Article  CAS  Google Scholar 

  13. Yaffe, M. B. et al. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell 91, 961–971 (1997)

    Article  CAS  Google Scholar 

  14. Chatr-aryamontri, A. et al. VirusMINT: a viral protein interaction database. Nucleic Acids Res. 37, D669–D673 (2009)

    Article  CAS  Google Scholar 

  15. Brass, A. L. et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319, 921–926 (2008)

    Article  ADS  CAS  Google Scholar 

  16. König, R. et al. Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 135, 49–60 (2008)

    Article  Google Scholar 

  17. Yeung, M. L., Houzet, L., Yedavalli, V. S. & Jeang, K. T. A genome-wide short hairpin RNA screening of Jurkat T-cells for human proteins contributing to productive HIV-1 replication. J. Biol. Chem. 284, 19463–19473 (2009)

    Article  CAS  Google Scholar 

  18. Zhou, H. et al. Genome-scale RNAi screen for host factors required for HIV replication. Cell Host Microbe 4, 495–504 (2008)

    Article  CAS  Google Scholar 

  19. Ruepp, A. et al. CORUM: the comprehensive resource of mammalian protein complexes–2009. Nucleic Acids Res. 38, D497–D501 (2010)

    Article  CAS  Google Scholar 

  20. Stark, C. et al. BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 34, D535–D539 (2006)

    Article  CAS  Google Scholar 

  21. Fahey, M. E. et al. GPS-Prot: a web-based visualization platform for integrating host-pathogen interaction data. BMC Bioinformatics 12, 298 (2011)

    Article  Google Scholar 

  22. Hinnebusch, A. G. eIF3: a versatile scaffold for translation initiation complexes. Trends Biochem. Sci. 31, 553–562 (2006)

    Article  CAS  Google Scholar 

  23. Alvarez, E., Castello, A., Menendez-Arias, L. & Carrasco, L. HIV protease cleaves poly(A)-binding protein. Biochem. J. 396, 219–226 (2006)

    Article  CAS  Google Scholar 

  24. Strack, P. R. et al. Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2. Proc. Natl Acad. Sci. USA 93, 9571–9576 (1996)

    Article  ADS  CAS  Google Scholar 

  25. Schilling, O. & Overall, C. M. Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites. Nature Biotechnol. 26, 685–694 (2008)

    Article  CAS  Google Scholar 

  26. Asano, K. et al. Structure of cDNAs encoding human eukaryotic initiation factor 3 subunits. Possible roles in RNA binding and macromolecular assembly. J. Biol. Chem. 272, 27042–27052 (1997)

    Article  CAS  Google Scholar 

  27. Valente, S. T., Gilmartin, G. M., Mott, C., Falkard, B. & Goff, S. P. Inhibition of HIV-1 replication by eIF3f. Proc. Natl Acad. Sci. USA 106, 4071–4078 (2009)

    Article  ADS  CAS  Google Scholar 

  28. Jäger, S. et al. Vif hijacks CBF-β to degrade APOBEC3G and promote HIV-1 infection. Naturehttp://dx.doi.org/10.1038/nature10693 (this issue).

  29. Zhou, M. et al. Mass spectrometry reveals modularity and a complete subunit interaction map of the eukaryotic translation factor eIF3. Proc. Natl Acad. Sci. USA 105, 18139–18144 (2008)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Choi, Z. Rizvi and E. Kwon for cloning of human genes and J. Cate for purified eIF3. We also thank J. Gross, R. Andino, R. Harris, M. Daugherty and members of the Krogan lab for discussion. This research was funded by grants from QB3@UCSF and the National Institutes of Health (P50 GM082250 to N.J.K., A.D.F., C.S.C. and T.A.; P01 AI090935 to N.J.K., S.K.C., J.A.Y. and F.D.B.; P50 GM081879 to N.J.K. and A.B.; P50 GM082545 to W.I.S.; P41RR001614 to A.B.; U54 RR022220 to A.S.; P01 GM073732-05 to A.T.; CHRP-ID08-TBI-063 to S.K.C.; P41 RR001081 to J.H.M.) and from the Nomis Foundation (to J.A.Y.). N.J.K. is a Searle Scholar and a Keck Young Investigator.

Author information

Author notes

  1. Iván D’Orso

    Present address: Present address: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA, 75390,

Authors and Affiliations

  1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94158, California, USA

    Stefanie Jäger, Natali Gulbahce, Jeffrey R. Johnson, Kathryn E. McGovern, Michael Shales, Kathy Li, Hilda Hernandez, Gwendolyn M. Jang, Marie Fahey, Cathal Mahon & Nevan J. Krogan

  2. California Institute for Quantitative Biosciences, QB3, San Francisco, 94158, California, USA

    Stefanie Jäger, Peter Cimermancic, Natali Gulbahce, Jeffrey R. Johnson, Kathryn E. McGovern, Michael Shales, Kathy Li, Hilda Hernandez, Gwendolyn M. Jang, Eyal Akiva, Marie Fahey, Cathal Mahon, Tanja Kortemme, Ryan D. Hernandez, Charles S. Craik, Alma Burlingame, Andrej Sali, Alan D. Frankel & Nevan J. Krogan

  3. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 94158, California, USA

    Peter Cimermancic, Eyal Akiva, Tanja Kortemme, Ryan D. Hernandez & Andrej Sali

  4. J. David Gladstone Institutes, San Francisco, 94158, California, USA

    Jeffrey R. Johnson & Nevan J. Krogan

  5. Department of Pharmaceutical Chemistry, University of California, San Francisco, 94158, California, USA

    Starlynn C. Clarke, Kathy Li, Hilda Hernandez, Cathal Mahon, Anthony J. O’Donoghue, John H. Morris, David A. Maltby, Charles S. Craik, Alma Burlingame & Andrej Sali

  6. Department of Biochemistry, University of Utah, Salt Lake City, 84112, Utah, USA

    Gaelle Mercenne & Wesley I. Sundquist

  7. Sanford-Burnham Medical Research Institute, La Jolla, 92037, California, USA

    Lars Pache & Sumit K. Chanda

  8. Department of Biochemistry and Biophysics, University of California, San Francisco, 94158, California, USA

    Gwendolyn M. Jang, Iván D’Orso, Jason Fernandes & Alan D. Frankel

  9. Department of Microbiology, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Shoshannah L. Roth, Melanie Stephens & Frederic D. Bushman

  10. The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    John Marlett & John A. Young

  11. Department of Chemistry, University of California, Berkeley, 94720, California, USA

    Aleksandar Todorovic

  12. Department of Molecular and Cell Biology, University of California, Berkeley, 94720, California, USA

    Tom Alber

  13. Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland ,

    Gerard Cagney

  14. Host Pathogen Circuitry Group, University of California, San Francisco, 94158, California, USA

    Tanja Kortemme, Ryan D. Hernandez, Andrej Sali, Alan D. Frankel & Nevan J. Krogan

Authors
  1. Stefanie Jäger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Cimermancic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natali Gulbahce
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeffrey R. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathryn E. McGovern
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Starlynn C. Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Shales
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gaelle Mercenne
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lars Pache
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kathy Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hilda Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gwendolyn M. Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shoshannah L. Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Eyal Akiva
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. John Marlett
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Melanie Stephens
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Iván D’Orso
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jason Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Marie Fahey
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Cathal Mahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Anthony J. O’Donoghue
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Aleksandar Todorovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. John H. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. David A. Maltby
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Tom Alber
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Gerard Cagney
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Frederic D. Bushman
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. John A. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Sumit K. Chanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Wesley I. Sundquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Tanja Kortemme
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Ryan D. Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Charles S. Craik
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Alma Burlingame
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Andrej Sali
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Alan D. Frankel
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Nevan J. Krogan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.J. generated the protein–protein interaction map; P.C. developed the MiST scoring system; N.G., M. Shales, E.A., M.F., J.H.M., J.R.J. and R.D.H. provided computational support; K.E.M., K.L., J.R.J., H.H., G.M.J., I.D., J.F. and D.A.M. provided experimental support; S.J., S.C.C., A.J.O. and A.T. characterized the PR–eIF3d interaction; S.J., G.M.J., C.M. and G.M. confirmed the interactions by immunoprecipitation/western blot; L.P., S.L.R., J.M. and M. Stephens used RNAi for functional verification; T.A., G.C., F.D.B., J.A.Y., S.K.C., W.I.S., T.K., R.D.H., C.S.C., A.B., A.S., A.D.F. and N.J.K. supervised the research; and S.J., P.C., A.S. and N.J.K. wrote the manuscript.

Corresponding author

Correspondence to Nevan J. Krogan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-20 with legends, Supplementary Tables 1-14, Supplementary Methods, a Supplementary Discussion and Supplementary References. (PDF 5928 kb)

Supplementary Data 1

The data shows raw MS data. (XLS 10886 kb)

Supplementary Data 2

The data shows three components used for MiST scoring. (XLS 1860 kb)

Supplementary Data 3

The data shows MiST scored MS data (>0.75 and full list). (XLS 1619 kb)

Supplementary Data 4

The data shows functional enrichment of host factors. (XLS 223 kb)

Supplementary Data 5

The data shows VirusMint PPIs. (XLS 115 kb)

Supplementary Data 6

The data shows overlap of VirusMint with all MiST scores. (XLS 28 kb)

Supplementary Data 7

The data shows published RNAi screens. (XLS 109 kb)

Supplementary Data 8

The data shows overlap of RNAi screens with all MiST scores. (XLS 210 kb)

Supplementary Data 9

The data shows human-human PPIs used in HIV-human network representation. (XLS 44 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jäger, S., Cimermancic, P., Gulbahce, N. et al. Global landscape of HIV–human protein complexes. Nature 481, 365–370 (2012). https://doi.org/10.1038/nature10719

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10719

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