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.

  • Full Paper
  • Published:

Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression

Genes & Immunity volume 6, pages 683–690 (2005)Cite this article

Abstract

Variation in the host response to infection by pathogens including HIV-1 may be conferred by polymorphic genetic factors such as HLA and killer immunoglobulin-like receptors (KIR) genes. Here, we examined KIR and HLA genotype effects on pretreatment viral load, rate of CD4+ T-cell decline and progression to AIDS among adult HIV-1-infected patients within the Western Australian HIV Study Cohort. In this study, carriage of KIR genes within the ‘B’ haplotype (eg KIR2DS2) was specifically associated with a more rapid CD4+ T-cell decline over time and progression to AIDS. In contrast, KIR gene repertoire had no effect on pretreatment viral load while selected HLA alleles (eg HLA-B*5701, HLA-B*2705) demonstrated significant protective effects on viremia. Furthermore, interactions between specific HLA and KIR genes did appear to influence HIV disease progression. The results suggest that host genetic variation within the HLA and KIR gene complexes have clinically relevant effects on the course of HIV-1/AIDS, acting independently as well as synergistically to modify disease progression at multiple levels.

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
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Nolan D, Gaudieri S, John M, Mallal S . Impact of host genetics on HIV disease progression and treatment: new conflicts on an ancient battleground. AIDS 2004; 18: 1231–1240.

    Article  CAS  Google Scholar 

  2. Tang J, Kaslow RA . The impact of host genetics on HIV infection and disease progression in the era of highly active antiretroviral therapy. AIDS 2003; 17 (Suppl 4): S51–S60.

    Article  Google Scholar 

  3. Chouquet C, Autran B, Gomard E et al. Correlation between breadth of memory HIV-specific cytotoxic T-cells, viral load and disease progression in HIV infection. AIDS 2002; 16: 2399–2407.

    Article  CAS  Google Scholar 

  4. Moore CB, John M, James IR, Christiansen FT, Witt CS, Mallal SA . Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 2002; 96: 1439–1443.

    Article  Google Scholar 

  5. Ho DD . Viral counts count in HIV infection. Science 1996; 272: 1124–1125.

    Article  CAS  Google Scholar 

  6. O'Brien TR, Blattner WA, Waters D et al. Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study. JAMA 1996; 276: 105–110.

    Article  CAS  Google Scholar 

  7. Lyles RH, Munoz A, Yamashita TE et al. Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. J Infect Dis 2000; 181: 872–880.

    Article  CAS  Google Scholar 

  8. Steel CM, Ludlam CA, Beatson D et al. HLA haplotype A1 B8 DR3 as a risk factor for HIV-related disease. Lancet 1988; 1: 1185–1188.

    Article  CAS  Google Scholar 

  9. Mallal S, Cameron PU, French MA, Dawkins RL . MHC genes and HIV infection. Lancet 1990; 335: 1591–1592.

    Article  CAS  Google Scholar 

  10. Kaslow RA, Carrington M, Apple R et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 1996; 2: 405–411.

    Article  CAS  Google Scholar 

  11. Flores-Villanueva PO, Hendel H, Caillat-Zucman S et al. Associations of MHC ancestral haplotypes with resistance/susceptibility to AIDS disease development. J Immunol 2003; 170: 1925–1929.

    Article  CAS  Google Scholar 

  12. Witt CS, Dewing C, Sayer DC, Uhrberg M, Parham P, Christiansen FT . Population frequencies and putative haplotypes of the killer cell immunoglobulin-like receptor sequences and evidence for recombination. Transplantation 1999; 68: 1784–1789.

    Article  CAS  Google Scholar 

  13. Martin AM, Freitas EM, Witt CS, Christiansen FT . The genomic organization and evolution of the natural killer immunoglobulin-like receptor (KIR) gene cluster. Immunogenetics 2000; 51: 268–280.

    Article  CAS  Google Scholar 

  14. Hsu K, Liu XR, Selvakumar A, Mickelson E, O'Reilly RJ, Dupont B . Killer Ig-like receptor haplotype analysis by gene content: evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. J Immunol 2002; 169: 5118–5129.

    Article  Google Scholar 

  15. Martin AM, Kulski JK, Gaudieri S et al. Comparative genomic analysis, diversity and evolution of two KIR haplotypes A and B. Gene 2004; 335: 121–131.

    Article  CAS  Google Scholar 

  16. Dawkins R, Leelayuwat C, Gaudieri S et al. Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease. Immunol Rev 1999; 167: 275–304.

    Article  CAS  Google Scholar 

  17. Price P, Witt C, Allcock R et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev 1999; 167: 257–274.

    Article  CAS  Google Scholar 

  18. Martin MP, Nelson G, Lee JH et al. Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. J Immunol 2002; 169: 2818–2822.

    Article  CAS  Google Scholar 

  19. van der Slik AR, Koeleman BP, Verduijn W, Bruining GJ, Roep BO, Giphart MJ . KIR in type 1 diabetes: disparate distribution of activating and inhibitory natural killer cell receptors in patients vs HLA-matched control subjects. Diabetes 2003; 52: 2639–2642.

    Article  CAS  Google Scholar 

  20. Khakoo SI, Thio CL, Martin MP et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 2004; 305: 872–874.

    Article  CAS  Google Scholar 

  21. Lanier LL . NK cell receptors. Annu Rev Immunol 1998; 16: 359–393.

    Article  CAS  Google Scholar 

  22. Collins KL, Chen BK, Kalams SA, Walker BD, Baltimore D . HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 1998; 391: 397–401.

    Article  CAS  Google Scholar 

  23. Cohen GB, Gandhi RT, Davis DM et al. The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity 1999; 10: 661–671.

    Article  CAS  Google Scholar 

  24. Lorenzo ME, Jung JU, Ploegh HL . Kaposi's sarcoma-associated herpesvirus K3 utilizes the ubiquitin–proteasome system in routing class major histocompatibility complexes to late endocytic compartments. J Virol 2002; 76: 5522–5531.

    Article  CAS  Google Scholar 

  25. Means RE, Ishido S, Alvarez X, Jung JU . Multiple endocytic trafficking pathways of MHC class I molecules induced by a Herpesvirus protein. EMBO J 2002; 21: 1638–1649.

    Article  CAS  Google Scholar 

  26. Ward JP, Bonaparte MI, Barker E . HLA-C and HLA-E reduce antibody-dependent natural killer cell-mediated cytotoxicity of HIV-infected primary T cell blasts. AIDS 2004; 18: 1769–1779.

    Article  Google Scholar 

  27. Bonaparte MI, Barker E . Killing of human immunodeficiency virus-infected primary T-cell blasts by autologous natural killer cells is dependent on the ability of the virus to alter the expression of major histocompatibility complex class I molecules. Blood 2004; 104: 2087–2094.

    Article  CAS  Google Scholar 

  28. Long EO, Burshtyn DN, Clark WP et al. Killer cell inhibitory receptors: diversity, specificity, and function. Immunol Rev 1997; 155: 135–144.

    Article  CAS  Google Scholar 

  29. Martin MP, Gao X, Lee JH et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 2002; 31: 429–434.

    Article  CAS  Google Scholar 

  30. Mallal SA . The Western Australian HIV Cohort Study. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17: S23–S27.

    Article  Google Scholar 

  31. Carrington M, Nelson G, O'Brien SJ . Considering genetic profiles in functional studies of immune responsiveness to HIV-1. Immunol Lett 2001; 79: 131–140.

    Article  CAS  Google Scholar 

  32. Khakoo SI, Carrington M . Receptors mediating interactions between natural killer cells and their viral associates. ASHI Quarterly 2004: 126–129.

  33. Gaudieri S, Nolan D, McKinnon E, Witt CS, Mallal S, Christiansen FT . Associations between KIR epitopes combinations expressed by HLA-B/-C haplotypes found in an HIV-1 infected study population may influence NK mediated immune responses. Mol Immunol 2005; 42: 557–560.

    Article  CAS  Google Scholar 

  34. Garcia CA, Robinson J, Guethlein LA, Parham P, Madrigal JA, Marsh SG . Human KIR sequences 2003. Immunogenetics 2003; 55: 227–239.

    Article  CAS  Google Scholar 

  35. Witt CS, Price P, Kaur G et al. Common HLA-B8-DR3 haplotype in Northern India is different from that found in Europe. Tissue Antigens 2002; 60: 474–480.

    Article  CAS  Google Scholar 

  36. Witt CS, Goodridge J, Gerbase-DeLima MG, Daher S, Christiansen FT . Maternal KIR repertoire is not associated with recurrent spontaneous abortion. Hum Reprod 2004; 19: 2653–2657.

    Article  CAS  Google Scholar 

  37. Uhrberg M, Valiante NM, Shum BP et al. Human diversity in killer cell inhibitory receptor genes. Immunity 1997; 7: 753–763.

    Article  CAS  Google Scholar 

  38. Norman PJ, Stephens HA, Verity DH, Chandanayingyong D, Vaughan RW . Distribution of natural killer cell immunoglobulin-like receptor sequences in three ethnic groups. Immunogenetics 2001; 52: 195–205.

    Article  CAS  Google Scholar 

  39. Gomez-Lozano N, Vilches C . Genotyping of human killer-cell immunoglobulin-like receptor genes by polymerase chain reaction with sequence-specific primers: An update. Tissue Antigens 2002; 59: 184–193.

    Article  CAS  Google Scholar 

  40. Cavalli-Sforza LL, Bodmer WF . The Genetics of Human Populations. WH Freeman and Company: San Francisco, 1971.

    Google Scholar 

  41. Grambsch P, Thernau T . Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994; 81: 515–526.

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge the support of the Western Australian HIV cohort and the staff at the Department of Clinical Immunology and Biochemical Genetics (DCIBG), Royal Perth Hospital, Western Australia. We thank Dr Elizabeth Freitas, Filipa Carvalho and Annette Patterson for their contribution. SG is supported by a Healy Fellowship from the Raine Medical Research Foundation.DD and EM equally contributed to the work described in this manuscript. Part of this work was supported by the National Health and Medical Research Council Grant Number 237412.

Author information

Authors and Affiliations

  1. Centre for Clinical Immunology and Biomedical Statistics, Murdoch University and Royal Perth Hospital, Western Australia, Australia

    S Gaudieri, E McKinnon, C Moore, D Nolan & S A Mallal

  2. Centre for Forensic Science, School of Anatomy and Human Biology, University of Western Australia, Western Australia, Australia

    S Gaudieri

  3. Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Western Australia, Australia

    D DeSantis, C S Witt, S A Mallal & F T Christiansen

  4. School of Surgery and Pathology, University of Western Australia, Western Australia, Australia

    D DeSantis & F T Christiansen

  5. Mathematics and Statistics, Murdoch University, Western Australia, Australia

    E McKinnon

Authors
  1. S Gaudieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D DeSantis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E McKinnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Nolan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C S Witt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S A Mallal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F T Christiansen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F T Christiansen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gaudieri, S., DeSantis, D., McKinnon, E. et al. Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression. Genes Immun 6, 683–690 (2005). https://doi.org/10.1038/sj.gene.6364256

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364256

Keywords

This article is cited by

Search

Advanced search

Quick links