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.

  • Original Article
  • Published:

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

Genes & Immunity volume 9, pages 69–80 (2008)Cite this article

Abstract

In both human immunodeficiency virus-infected humans and simian immunodeficiency virus (SIV)-infected macaques, genes encoded in the major histocompatibility complex (MHC) class I region are important determinants of disease progression. However, compared to the human human lymphocyte antigen complex, the macaque MHC region encodes many more class I genes. Macaques with the same immunodominant class I genes express additional Mhc genes with the potential to influence the disease course. We therefore assessed the association between of the Mhc class I haplotypes, rather than single gene variants, and survival time in SIV-infected rhesus macaques (Macaca mulatta). DNA sequence analysis and Mhc genotyping of 245 pedigreed monkeys identified 17 Mhc class I haplotypes that constitute 10 major genotypes. Among 81 vaccination-naive, SIV-infected macaques, 71 monkeys carried at least one Mhc class I haplotype encoding only MHC antigens that were incapable of inducing an effective anti-SIV cytotoxic T lymphocytes response. Study of these macaques enabled us to relate individual Mhc class I haplotypes to slow, medium and rapid disease progression. In a post hoc analysis, classification according to disease progression was found to explain at least 48% of the observed variation of survival time.

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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Bontrop RE, Watkins DI . MHC polymorphism: AIDS susceptibility in non-human primates. Trends Immunol 2005; 26: 227–233.

    Article  CAS  Google Scholar 

  2. Kaslow RA, Dorak T, Tang JJ . Influence of host genetic variation on susceptibility to HIV type 1 infection. J Infect Dis 2005; 191 (Suppl 1): S68–S77.

    Article  Google Scholar 

  3. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994; 68: 4650–4655.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB . Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 1994; 68: 6103–6110.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Yasutomi Y, Reimann KA, Lord CI, Miller MD, Letvin NL . Simian immunodeficiency virus-specific CD8+ lymphocyte response in acutely infected rhesus monkeys. J Virol 1993; 67: 1707–1711.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kuroda MJ, Schmitz JE, Charini WA, Nickerson CE, Lifton MA, Lord CI et al. Emergence of CTL coincides with clearance of virus during primary simian immunodeficiency virus infection in rhesus monkeys. J Immunol 1999; 162: 5127–5133.

    CAS  PubMed  Google Scholar 

  7. Goulder PJ, Phillips RE, Colbert RA, McAdam S, Ogg G, Nowak MA et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 1997; 3: 212–217.

    Article  CAS  Google Scholar 

  8. Price DA, Goulder PJ, Klenerman P, Sewell AK, Easterbrook PJ, Troop M et al. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci USA 1997; 94: 1890–1895.

    Article  CAS  Google Scholar 

  9. Klein MR, van Baalen CA, Holwerda AM, Kerkhof Garde SR, Bende RJ, Keet IP et al. Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med 1995; 181: 1365–1372.

    Article  CAS  Google Scholar 

  10. Barouch DH, Kunstman J, Kuroda MJ, Schmitz JE, Santra S, Peyerl FW et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 2002; 415: 335–339.

    Article  CAS  Google Scholar 

  11. Allen TM, O'Connor DH, Jing P, Dzuris JL, Mothe BR, Vogel TU et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 2000; 407: 386–390.

    Article  CAS  Google Scholar 

  12. O'Connor DH, Allen TM, Vogel TU, Jing P, DeSouza IP, Dodds E et al. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat Med 2002; 8: 493–499.

    Article  CAS  Google Scholar 

  13. O'Connor DH, Mothe BR, Weinfurter JT, Fuenger S, Rehrauer WM, Jing P et al. Major histocompatibility complex class I alleles associated with slow simian immunodeficiency virus disease progression bind epitopes recognized by dominant acute-phase cytotoxic-T-lymphocyte responses. J Virol 2003; 77: 9029–9040.

    Article  CAS  Google Scholar 

  14. Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J et al. Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 1999; 189: 991–998.

    Article  CAS  Google Scholar 

  15. Matano T, Shibata R, Siemon C, Connors M, Lane HC, Martin MA . Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 1998; 72: 164–169.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999; 283: 857–860.

    Article  CAS  Google Scholar 

  17. Kaslow RA, Carrington M, Apple R, Park L, Munoz A, Saah AJ 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 

  18. McNeil AJ, Yap PL, Gore SM, Brettle RP, McColl M, Wyld R et al. Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease. QJM 1996; 89: 177–185.

    Article  CAS  Google Scholar 

  19. Mann DL, Garner RP, Dayhoff DE, Cao K, Fernandez-Vina MA, Davis C et al. Major histocompatibility complex genotype is associated with disease progression and virus load levels in a cohort of human immunodeficiency virus type 1-infected Caucasians and African Americans. J Infect Dis 1998; 178: 1799–1802.

    Article  CAS  Google Scholar 

  20. Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, Goedert JJ et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 1999; 283: 1748–1752.

    Article  CAS  Google Scholar 

  21. Daza-Vamenta R, Glusman G, Rowen L, Guthrie B, Geraghty DE . Genetic divergence of the rhesus macaque major histocompatibility complex. Genome Res 2004; 14: 1501–1515.

    Article  CAS  Google Scholar 

  22. Shiina T, Ota M, Shimizu S, Katsuyama Y, Hashimoto N, Takasu M et al. Rapid evolution of major histocompatibility complex class I genes in primates generates new disease alleles in humans via hitchhiking diversity. Genetics 2006; 173: 1555–1570.

    Article  CAS  Google Scholar 

  23. Boyson JE, Shufflebotham C, Cadavid LF, Urvater JA, Knapp LA, Hughes AL et al. The MHC class I genes of the rhesus monkey. Different evolutionary histories of MHC class I and II genes in primates. J Immunol 1996; 156: 4656–4665.

    CAS  PubMed  Google Scholar 

  24. Otting N, Heijmans CM, Noort RC, de Groot NG, Doxiadis GG, van Rood JJ et al. Unparalleled complexity of the MHC class I region in rhesus macaques. Proc Natl Acad Sci USA 2005; 102: 1626–1631.

    Article  CAS  Google Scholar 

  25. Muhl T, Krawczak M, Ten Haaft P, Hunsmann G, Sauermann U . MHC class I alleles influence set-point viral load and survival time in simian immunodeficiency virus-infected rhesus monkeys. J Immunol 2002; 169: 3438–3446.

    Article  CAS  Google Scholar 

  26. Pal R, Venzon D, Letvin NL, Santra S, Montefiori DC, Miller NR et al. ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency. J Virol 2002; 76: 292–302.

    Article  CAS  Google Scholar 

  27. Yant LJ, Friedrich TC, Johnson RC, May GE, Maness NJ, Enz AM et al. The high-frequency major histocompatibility complex class I allele Mamu-B*17 is associated with control of simian immunodeficiency virus SIVmac239 replication. J Virol 2006; 80: 5074–5077.

    Article  CAS  Google Scholar 

  28. Wojcechowskyj JA, Yant LJ, Wiseman RW, O'Connor S L, O'Connor DH . Control of SIVmac239 is not predicted by inheritance of Mamu-B*17-containing haplotypes. J Virol 2007; 81: 406–410.

    Article  CAS  Google Scholar 

  29. Khazand M, Peiberg C, Nagy M, Sauermann U . Mhc-DQ-DRB haplotype analysis in the rhesus macaque: evidence for a number of different haplotypes displaying a low allelic polymorphism. Tissue Antigens 1999; 54: 615–624.

    Article  CAS  Google Scholar 

  30. Sauermann U . DQ-haplotype analysis in rhesus macaques: implications for the evolution of these genes. Tissue Antigens 1998; 52: 550–557.

    Article  CAS  Google Scholar 

  31. Krebs KC, Jin Z, Rudersdorf R, Hughes AL, O'Connor DH . Unusually high frequency MHC class I alleles in Mauritian origin cynomolgus macaques. J Immunol 2005; 175: 5230–5239.

    Article  CAS  Google Scholar 

  32. Robinson S, Charini WA, Newberg MH, Kuroda MJ, Lord CI, Letvin NL . A commonly recognized simian immunodeficiency virus Nef epitope presented to cytotoxic T lymphocytes of Indian-origin rhesus monkeys by the prevalent major histocompatibility complex class I allele Mamu-A*02. J Virol 2001; 75: 10179–10186.

    Article  CAS  Google Scholar 

  33. Loffredo JT, Sidney J, Wojewoda C, Dodds E, Reynolds MR, Napoe G . Identification of seventeen new simian immunodeficiency virus-derived CD8+ T cell epitopes restricted by the high frequency molecule, Mamu-A*02, and potential escape from CTL recognition. J Immunol 2004; 173: 5064–5076.

    Article  CAS  Google Scholar 

  34. Allen TM, Mothe BR, Sidney J, Jing P, Dzuris JL, Liebl ME et al. CD8(+) lymphocytes from simian immunodeficiency virus-infected rhesus macaques recognize 14 different epitopes bound by the major histocompatibility complex class I molecule Mamu-A*01: implications for vaccine design and testing. J Virol 2001; 75: 738–749.

    Article  CAS  Google Scholar 

  35. Sidney J, Dzuris JL, Newman MJ, Johnson RP, Kaur A, Amitinder K et al. Definition of the Mamu A*01 peptide binding specificity: application to the identification of wild-type and optimized ligands from simian immunodeficiency virus regulatory proteins. J Immunol 2000; 165: 6387–6399.

    Article  CAS  Google Scholar 

  36. Sauermann U, Stahl-Hennig C, Stolte N, Muhl T, Krawczak M, Spring M et al. Homozygosity for a conserved Mhc class II DQ-DRB haplotype is associated with rapid disease progression in simian immunodeficiency virus-infected macaques: results from a prospective study. J Infect Dis 2000; 182: 716–724.

    Article  CAS  Google Scholar 

  37. de Groot N, Doxiadis GG, De Groot NG, Otting N, Heijmans C, Rouweler AJ et al. Genetic makeup of the DR region in rhesus macaques: gene content, transcripts, and pseudogenes. J Immunol 2004; 172: 6152–6157.

    Article  CAS  Google Scholar 

  38. Evans DT, Knapp LA, Jing P, Mitchen JL, Dykhuizen M, Montefiori DC et al. Rapid and slow progressors differ by a single MHC class I haplotype in a family of MHC-defined rhesus macaques infected with SIV. Immunol Lett 1999; 66: 53–59.

    Article  CAS  Google Scholar 

  39. Cullen M, Perfetto SP, Klitz W, Nelson G, Carrington M . High-resolution patterns of meiotic recombination across the human major histocompatibility complex. Am J Hum Genet 2002; 71: 759–776.

    Article  Google Scholar 

  40. Loffredo JT, Sidney J, Piaskowski S, Szymanski A, Furlott J, Rudersdorf R . The high frequency Indian rhesus macaque MHC class I molecule, Mamu-B*01, does not appear to be involved in CD8+ T lymphocyte responses to SIVmac239. J Immunol 2005; 175: 5986–5997.

    Article  CAS  Google Scholar 

  41. Newberg MH, McEvers KJ, Gorgone DA, Lifton MA, Baumeister SH, Veazey RS et al. Immunodomination in the evolution of dominant epitope-specific CD8+ T lymphocyte responses in simian immunodeficiency virus-infected rhesus monkeys. J Immunol 2006; 176: 319–328.

    Article  CAS  Google Scholar 

  42. Yang OO, Church J, Kitchen CM, Kilpatrick R, Ali A, Geng Y et al. Genetic and stochastic influences on the interaction of human immunodeficiency virus type 1 and cytotoxic T lymphocytes in identical twins. J Virol 2005; 79: 15368–15375.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  44. Lopez-Vazquez A, Mina-Blanco A, Martinez-Borra J, Njobvu PD, Suarez-Alvarez B, Blanco-Gelaz MA et al. Interaction between KIR3DL1 and HLA-B*57 supertype alleles influences the progression of HIV-1 infection in a Zambian population. Hum Immunol 2005; 66: 285–289.

    Article  CAS  Google Scholar 

  45. Gaudieri S, DeSantis D, McKinnon E, Moore C, Nolan D, Witt CS et al. Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression. Genes Immun 2005; 6: 683–690.

    Article  CAS  Google Scholar 

  46. Qi Y, Martin MP, Gao X, Jacobson L, Goedert JJ, Buchbinder S et al. KIR/HLA pleiotropism: protection against both HIV and opportunistic infections. PLoS Pathog 2006; 2: e79.

    Article  Google Scholar 

  47. Jennes W, Verheyden S, Demanet C, Adje-Toure CA, Vuylsteke B, Nkengasong JN et al. Cutting Edge: resistance to HIV-1 infection among African female sex workers is associated with inhibitory KIR in the absence of their HLA ligands. J Immunol 2006; 177: 6588–6592.

    Article  CAS  Google Scholar 

  48. Friedrich TC, Valentine LE, Yant LJ, Rakasz EG, Piaskowski SM, Furlott JR et al. Subdominant CD8+ T-cell responses are involved in durable control of AIDS virus replication. J Virol 2007; 81: 3465–3476.

    Article  CAS  Google Scholar 

  49. Nurnberg P, Sauermann U, Kayser M, Lanfer C, Manz E, Widdig A et al. Paternity assessment in rhesus macaques (Macaca mulatta): multilocus DNA fingerprinting and PCR marker typing. Am J Primatol 1998; 44: 1–18.

    Article  CAS  Google Scholar 

  50. Suh YS, Park KS, Sauermann U, Franz M, Norley S, Wilfingseder D et al. Reduction of viral loads by multigenic DNA priming and adenovirus boosting in the SIVmac-macaque model. Vaccine 2006; 24: 1811–1820.

    Article  CAS  Google Scholar 

  51. Dykhuizen M, Mitchen JL, Montefiori DC, Thomson J, Acker L, Lardy H et al. Determinants of disease in the simian immunodeficiency virus-infected rhesus macaque: characterizing animals with low antibody responses and rapid progression. J Gen Virol 1998; 79 (Part 10): 2461–2467.

    Article  CAS  Google Scholar 

  52. Hirsch VM, Santra S, Goldstein S, Plishka R, Buckler-White A, Seth A et al. Immune failure in the absence of profound CD4+ T-lymphocyte depletion in simian immunodeficiency virus-infected rapid progressor macaques. J Virol 2004; 78: 275–284.

    Article  CAS  Google Scholar 

  53. Dittmer U, Stahl-Hennig C, Coulibaly C, Nisslein T, Luke W, Fuchs D . Repeated exposure of rhesus macaques to low doses of simian immunodeficiency virus (SIV) did not protect them against the consequences of a high-dose SIV challenge. J Gen Virol 1995; 76 (Part 6): 1307–1315.

    Article  Google Scholar 

  54. Robinson J, Waller MJ, Parham P, de Groot N, Bontrop R, Kennedy LJ et al. IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 2003; 31: 311–314.

    Article  CAS  Google Scholar 

  55. Knapp LA, Cadavid LF, Eberle ME, Knechtle SJ, Bontrop RE, Watkins DI . Identification of new Mamu-DRB alleles using DGGE and direct sequencing. Immunogenetics 1997; 45: 171–179.

    Article  CAS  Google Scholar 

  56. Vigon N, Sauermann U . Sequence-based typing techniques for rhesus macaque MhcMamu-DQB1 allow the identification of more than 35 alleles. Tissue Antigens 2002; 59: 88–94.

    Article  CAS  Google Scholar 

  57. Negri DR, Baroncelli S, Catone S, Comini A, Michelini Z, Maggiorella MT . Protective efficacy of a multicomponent vector vaccine in cynomolgus monkeys after intrarectal simian immunodeficiency virus challenge. J Gen Virol 2004; 85: 1191–1201.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Sandra Heine and Judith Hampe for expert technical assistance and Dr Nicola Rose and Washingtone Oichieng for critical reading and very helpful comments on the manuscript. This work was supported by grants from the German Ministry of Education and Research 0313360 and 01GR0504 and by the European Union (EUPRIM-NET contract no. FP6-I3-026155).

Author information

Authors and Affiliations

  1. Department of Virology and Immunology, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany

    U Sauermann, N Leuchte, H Meyer, G Hunsmann & C Stahl-Hennig

  2. Genome Analysis, Leibniz Institute for Age Research, Jena, Germany

    R Siddiqui & M Platzer

  3. Division of Molecular and Life Sciences, Cellular Immunology Laboratory, Pohang University of Science and Technology, Pohang, Republic of Korea

    Y-S Suh

  4. Department of Infectious Pathology, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany

    K Mätz-Rensing

  5. Department of Hygiene, Microbiology and Social Medicine, Ludwig Boltzmann Institute for AIDS Research, Innsbruck Medical University, Innsbruck, Austria

    H Stoiber

  6. Cologne Center for Genomics, University of Cologne, Köln, Germany

    P Nürnberg

  7. Institute for Medical Informatics and Statistics, Christian-Albrechts-University, Kiel, Germany

    M Krawczak

Authors
  1. U Sauermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Siddiqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y-S Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Platzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Leuchte
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Mätz-Rensing
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Stoiber
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Nürnberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G Hunsmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C Stahl-Hennig
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Krawczak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to U Sauermann.

Additional information

Disclosure/conflict of interest

The authors declare that there are no conflicts of interest or any financial interest.

Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sauermann, U., Siddiqui, R., Suh, YS. et al. Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques. Genes Immun 9, 69–80 (2008). https://doi.org/10.1038/sj.gene.6364448

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364448

Keywords

This article is cited by

Search

Advanced search

Quick links