Skip to main content

Thank you for visiting 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.

HIV-1 adaptation to NK-cell-mediated immune pressure


Natural killer (NK) cells have an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors1,2,3. Epidemiological and functional studies have recently suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory killer immunoglobulin-like receptors (KIRs)4,5,6,7. However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. Here we describe KIR-associated amino-acid polymorphisms in the HIV-1 sequence of chronically infected individuals, on a population level. We show that these KIR-associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected CD4+ T cells, and reduce the antiviral activity of KIR-positive NK cells. These data demonstrate that KIR-positive NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK-cell-mediated immune pressure by selecting for sequence polymorphisms, as was previously described for virus-specific T cells and neutralizing antibodies8. NK cells might therefore have a previously underappreciated role in contributing to viral evolution.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: KIR2DL2-associated sequence polymorphisms result in a loss of inhibition of HIV replication by NK cells in vitro.
Figure 2: Amino-acid polymorphisms at positions 71 and 74 in Vpu inhibit KIR2DL2, but not KIR2DL3, recognition and binding.
Figure 3: Two additional KIR2DL2-associated amino-acid polymorphisms reduce KIR2DL2-mediated NK-cell recognition of virally infected cells.
Figure 4: KIR2DL2-associated amino-acid polymorphisms affect binding of KIR2DL2, but not KIR2DL3, to infected CD4 + T cells.


  1. Lanier, L. L. Up on the tightrope: natural killer cell activation and inhibition. Nature Immunol. 9, 495–502 (2008)

    Article  CAS  Google Scholar 

  2. Yokoyama, W. M. Specific and non-specific natural killer cell responses to viral infection. Adv. Exp. Med. Biol. 560, 57–61 (2005)

    Article  CAS  Google Scholar 

  3. Lanier, L. L. NK cell recognition. Annu Rev Immunol 23, 225–274 (2004)

    Article  Google Scholar 

  4. Martin, M. P. et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nature Genet. 31, 429–434 (2002)

    Article  CAS  Google Scholar 

  5. Martin, M. P. et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nature Genet. 39, 733–740 (2007)

    Article  CAS  Google Scholar 

  6. Alter, G. et al. Differential natural killer cell mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J. Exp. Med. 204, 3027–3036 (2007)

    Article  CAS  Google Scholar 

  7. Altfeld, M. & Goulder, P. ‘Unleashed’ natural killers hinder HIV. Nature Genet. 39, 708–710 (2007)

    Article  CAS  Google Scholar 

  8. Goulder, P. J. & Watkins, D. I. HIV and SIV CTL escape: implications for vaccine design. Nature Rev. Immunol. 4, 630–640 (2004)

    Article  CAS  Google Scholar 

  9. Wang, Y. E. et al. Protective HLA class I alleles that restrict acute-phase CD8+ T-cell responses are associated with viral escape mutations located in highly conserved regions of human immunodeficiency virus type 1. J. Virol. 83, 1845–1855 (2009)

    Article  CAS  Google Scholar 

  10. Carlson, J. M. et al. Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. PLOS Comput. Biol. 4, e1000225 (2008)

    Article  MathSciNet  Google Scholar 

  11. Schneidewind, A. et al. Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. J. Virol. 81, 12382–12393 (2007)

    Article  CAS  Google Scholar 

  12. Adachi, A. et al. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J. Virol. 59, 284–291 (1986)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Moesta, A. K. et al. Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3. J. Immunol. 180, 3969–3979 (2008)

    Article  CAS  Google Scholar 

  14. Stewart, C. A. et al. Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. Proc. Natl Acad. Sci. USA 102, 13224–13229 (2005)

    Article  ADS  CAS  Google Scholar 

  15. Stewart-Jones, G. B. et al. Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA-B*2705. Eur. J. Immunol. 35, 341–351 (2005)

    Article  CAS  Google Scholar 

  16. Boyington, J. C., Motyka, S. A., Schuck, P., Brooks, A. G. & Sun, P. D. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–543 (2000)

    Article  ADS  CAS  Google Scholar 

  17. Thananchai, H. et al. Cutting edge: allele-specific and peptide-dependent interactions between KIR3DL1 and HLA-A and HLA-B. J. Immunol. 178, 33–37 (2007)

    Article  CAS  Google Scholar 

  18. Rajagopalan, S. & Long, E. O. The direct binding of a p58 killer cell inhibitory receptor to human histocompatibility leukocyte antigen (HLA)-Cw4 exhibits peptide selectivity. J. Exp. Med. 185, 1523–1528 (1997)

    Article  CAS  Google Scholar 

  19. Malnati, M. S. et al. Peptide specificity in the recognition of MHC class I by natural killer cell clones. Science 267, 1016–1018 (1995)

    Article  ADS  CAS  Google Scholar 

  20. Peruzzi, M., Parker, K. C., Long, E. O. & Malnati, M. S. Peptide sequence requirements for the recognition of HLA-B*2705 by specific natural killer cells. J. Immunol. 157, 3350–3356 (1996)

    CAS  PubMed  Google Scholar 

  21. Mandelboim, O., Wilson, S. B., Vales-Gomez, M., Reyburn, H. T. & Strominger, J. L. Self and viral peptides can initiate lysis by autologous natural killer cells. Proc. Natl Acad. Sci. USA 94, 4604–4609 (1997)

    Article  ADS  CAS  Google Scholar 

  22. Mandelboim, O. et al. The binding site of NK receptors on HLA-C molecules. Immunity 6, 341–350 (1997)

    Article  CAS  Google Scholar 

  23. Fadda, L. et al. Common HIV-1 peptide variants mediate differential binding of KIR3DL1 to HLA-Bw4 molecules. J. Virol. 85, 5970–5974 (2011)

    Article  CAS  Google Scholar 

  24. Fadda, L. et al. Peptide antagonism as a mechanism for NK cell activation. Proc. Natl Acad. Sci. USA 107, 10160–10165 (2010)

    Article  ADS  CAS  Google Scholar 

  25. Le Gall, S., Stamegna, P. & Walker, B. D. Portable flanking sequences modulate CTL epitope processing. J. Clin. Invest. 117, 3563–3575 (2007)

    Article  CAS  Google Scholar 

  26. Ward, J. et al. HIV-1 Vpr triggers natural killer cell-mediated lysis of infected cells through activation of the ATR-mediated DNA damage response. PLoS Pathog. 5, e1000613 (2009)

    Article  Google Scholar 

  27. Ward, J. et al. HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts. Blood 110, 1207–1214 (2007)

    Article  CAS  Google Scholar 

  28. Khakoo, S. I. et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872–874 (2004)

    Article  ADS  CAS  Google Scholar 

  29. Alter, G., Malenfant, J. M. & Altfeld, M. CD107a as a functional marker for the identification of natural killer cell activity. J. Immunol. Methods 294, 15–22 (2004)

    Article  CAS  Google Scholar 

Download references


These studies were supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants R01 AI067031 (M.A.) and PO1 AI074415 (M.A. and T.M.A.), and by the Doris Duke Charitable Foundation (M.A.). This project was funded in whole or in part with federal funds from the National Cancer Institute (NIH) under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. S.I.K. is a recipient of a Wellcome Trust Senior Clinical Fellowship and M.A. is a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation. We thank Microsoft Research, the Bill & Melinda Gates Foundation, the Mark and Lisa Schwartz Foundation and the Phillip T. and Susan M. Ragon Foundation for their support.

Author information

Authors and Affiliations



G.A. conducted the immunology experiments and L.F. performed the KIR-staining experiments on T2 cell lines. A.S. and C.O.-N. constructed the viral variants. D.H., C.M.K. and J.M.C. performed the data analysis identifying KIR-associated polymorphisms. B.L. and T.M.A. performed the viral sequencing, M.C. and M.M. performed the HLA and KIR typing, and L.F. and S.I.K. provided the KIR fusion construct. G.A. and M.A. planned the studies, prepared the manuscript and supervised the project.

Corresponding author

Correspondence to Marcus Altfeld.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-4 with legends and Supplementary Tables 1-6. (PDF 639 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Alter, G., Heckerman, D., Schneidewind, A. et al. HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476, 96–100 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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.


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