, 60:339 | Cite as

MHC class I characterization of Indonesian cynomolgus macaques

  • Chad J. Pendley
  • Ericka A. Becker
  • Julie A. Karl
  • Alex J. Blasky
  • Roger W. Wiseman
  • Austin L. Hughes
  • Shelby L. O’Connor
  • David H. O’Connor
Original Paper


Cynomolgus macaques (Macaca fascicularis) are quickly becoming a useful model for infectious disease and transplantation research. Even though cynomolgus macaques from different geographic regions are used for these studies, there has been limited characterization of full-length major histocompatibility complex (MHC) class I immunogenetics of distinct geographic populations. Here, we identified 48 MHC class I cDNA nucleotide sequences in eleven Indonesian cynomolgus macaques, including 41 novel Mafa-A and Mafa-B sequences. We found seven MHC class I sequences in Indonesian macaques that were identical to MHC class I sequences identified in Malaysian or Mauritian macaques. Sharing of nucleotide sequences between these geographically distinct populations is also consistent with the hypothesis that Indonesia was a source of the Mauritian macaque population. In addition, we found that the Indonesian cDNA sequence Mafa-B*7601 is identical throughout its peptide binding domain to Mamu-B*03, an allele that has been associated with control of Simian immunodeficiency virus (SIV) viremia in Indian rhesus macaques. Overall, a better understanding of the MHC class I alleles present in Indonesian cynomolgus macaques improves their value as a model for disease research, and it better defines the biogeography of cynomolgus macaques throughout Southeast Asia.


MHC Immunogenetics Indonesia Macaca fascicularis 



This work was supported by 1 R24 RR021745-01A1. PCR-SSP assay development was supported by NIAID Contract number HHSN266200400088C/N01-AI-40088. Support to C.J.P. was made possible through funding for undergraduate research from the UW-Madison Hilldale Fund, and support to A.L.H. was provided by grant number GM43940 from the NIH. This publication was also made possible in part by grant number P51 RR000167 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), to the Wisconsin National Primate Research Center, University of Wisconsin—Madison. This research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grant numbers RR15459-01 and RR020141-01. This publication’s contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.

We thank the Washington Primate Research Center for providing blood samples from animals IN01 through 1N12 and the Cerus Corporation for providing PBMC from animals CE01 through CE30. We thank the MHC typing core at the Wisconsin Primate Research Center for typing the Indonesian cohort for Mamu-B*03. We acknowledge Natasja de Groot and the IMGT for assigning uniform allele nomenclature. Finally, we appreciate many members of the O’Connor lab for helpful discussions.


  1. Blancher A, Tisseyre P, Dutaur M, Apoil PA, Maurer C, Quesniaux V, Raulf F, Bigaud M, Abal M (2006) Study of Cynomolgus monkey (Macaca fascicularis) MhcDRB (Mafa-DRB) polymorphism in two populations. Immunogenetics 58:269–282PubMedCrossRefGoogle Scholar
  2. Bonhomme M, Blancher A, Jalil MF, Crouau-Roy B (2007) Factors shaping genetic variation in the MHC of natural non-human primate populations. Tissue Antigens 70:398–411PubMedCrossRefGoogle Scholar
  3. Bontrop RE, Watkins DI (2005) MHC polymorphism: AIDS susceptibility in non-human primates. Trends Immunol 26:227–233PubMedCrossRefGoogle Scholar
  4. Boyson JE, Shufflebotham C, Cadavid LF, Urvater JA, Knapp LA, Hughes AL, Watkins DI (1996) The MHC class I genes of the rhesus monkey. Different evolutionary histories of MHC class I and II genes in primates. J Immunol 156:4656–4665PubMedGoogle Scholar
  5. Capuano SVr, Croix DA, Pawar S, Zinovik A, Myers A, Lin PL, Bissel S, Fuhrman C, Klein E, Flynn JL (2003) Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect Immun 71:5831–5844PubMedCrossRefGoogle Scholar
  6. Carrington M, O, Brien SJ (2003) The influence of HLA genotype on AIDS. Annu Rev Med 54:535–551PubMedCrossRefGoogle Scholar
  7. Conlee KM, Hoffeld EH, Stephens ML (2004) A demographic analysis of primate research in the United States. ATLA Supplement 1:315–322Google Scholar
  8. Cooke GS, Hill AV (2001) Genetics of susceptibility to human infectious disease. Nat Rev Genet 2:967–977PubMedCrossRefGoogle Scholar
  9. Dzuris JL, Sidney J, Appella E, Chesnut RW, Watkins DI, Sette A (2000) Conserved MHC class I peptide binding motif between humans and rhesus macaques. J Immunol 164:283–291PubMedGoogle Scholar
  10. Emborg ME (2007) Nonhuman primate models of Parkinson’s disease. ILAR J 48:339–355PubMedGoogle Scholar
  11. Evans DT, O’ Connor DH, Jing P, Dzuris JL, Sidney J, da Silva J, Allen TM, Horton H, Venham JE, Rudersdorf RA, Vogel T, Pauza CD, Bontrop RE, DeMars R, Sette A, Hughes AL, Watkins DI (1999) Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef. Nat Med 5:1270–1276PubMedCrossRefGoogle Scholar
  12. Evans DT, Jing P, Allen TM, O’ Connor DH, Horton H, Venham JE, Piekarczyk M, Dzuris J, Dykhuzen M, Mitchen J, Rudersdorf RA, Pauza CD, Sette A, Bontrop RE, DeMars R, Watkins DI (2000) Definition of five new simian immunodeficiency virus cytotoxic T-lymphocyte epitopes and their restricting major histocompatibility complex class I molecules: evidence for an influence on disease progression. J Virol 74:7400–7410PubMedCrossRefGoogle Scholar
  13. Felsenstein J (1985) Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39:783–791CrossRefGoogle Scholar
  14. Florese R, Wiseman RW, Venzon D, Karl JA, Demberg T, Larsen K, Flanary L, Kalyanaraman VS, Pal R, Titti F, Patterson LJ, Heath MJ, O’Connor D, Cafaro A, Ensoli B, Robert-Guroff M (2008) Comparative study of Tat vaccine regimens in Mauritian cynomolgus and Indian rhesus macaques: Influence of Mauritian MHC haplotypes on susceptibility/resistance to SHIV89.6P infection. Vaccine (in press)Google Scholar
  15. Geretti AM, Hulskotte EG, Dings ME, van Baalen CA, van Amerongen G, Osterhaus AD (1997) CD8+ cytotoxic T lymphocytes of a cynomolgus macaque infected with simian immunodeficiency virus (SIV) mac32H-J5 recognize a nine amino acid epitope in SIV Gag p26. J Gen Virol 78:821–824PubMedGoogle Scholar
  16. Gibbs RA, Rogers J, Katze MG, Bumgarner R, Weinstock GM, Mardis ER, Remington KA, Strausberg RL, Venter JC, Wilson RK, Batzer MA, Bustamante CD, Eichler EE, Hahn MW, Hardison RC, Makova KD, Miller W, Milosavljevic A, Palermo RE, Siepel A, Sikela JM, Attaway T, Bell S, Bernard KE, Buhay CJ, Chandrabose MN, Dao M, Davis C, Delehaunty KD, Ding Y, Dinh HH, Dugan-Rocha S, Fulton LA, Gabisi RA, Garner TT, Godfrey J, Hawes AC, Hernandez J, Hines S, Holder M, Hume J, Jhangiani SN, Joshi V, Khan ZM, Kirkness EF, Cree A, Fowler RG, Lee S, Lewis LR, Li Z, Liu YS, Moore SM, Muzny D, Nazareth LV, Ngo DN, Okwuonu GO, Pai G, Parker D, Paul HA, Pfannkoch C, Pohl CS, Rogers YH, Ruiz SJ, Sabo A, Santibanez J, Schneider BW, Smith SM, Sodergren E, Svatek AF, Utterback TR, Vattathil S, Warren W, White CS, Chinwalla AT, Feng Y, Halpern AL, Hillier LW, Huang X, Minx P, Nelson JO, Pepin KH, Qin X, Sutton GG, Venter E, Walenz BP, Wallis JW, Worley KC, Yang SP, Jones SM, Marra MA, Rocchi M, Schein JE, Baertsch R, Clarke L, Csuros M, Glasscock J, Harris RA, Havlak P, Jackson AR, Jiang H, Liu Y, Messina DN, Shen Y, Song HX, Wylie T, Zhang L, Birney E, Han K, Konkel MK, Lee J, Smit AF, Ullmer B, Wang H, Xing J, Burhans R, Cheng Z, Karro JE, Ma J, Raney B, She X, Cox MJ, Demuth JP, Dumas LJ, Han SG, Hopkins J, Karimpour-Fard A, Kim YH, Pollack JR, Vinar T, Addo-Quaye C, Degenhardt J, Denby A, Hubisz MJ, Indap A, Kosiol C, Lahn BT, Lawson HA, Marklein A, Nielsen R, Vallender EJ, Clark AG, Ferguson B, Hernandez RD, Hirani K, Kehrer-Sawatzki H, Kolb J, Patil S, Pu LL, Ren Y, Smith DG, Wheeler DA, Schenck I, Ball EV, Chen R, Cooper DN, Giardine B, Hsu F, Kent WJ, Lesk A, Nelson DL, O, brien WE, Prufer K, Stenson PD, Wallace JC, Ke H, Liu XM, Wang P, Xiang AP, Yang F, Barber GP, Haussler D, Karolchik D, Kern AD, Kuhn RM, Smith KE, Zwieg AS (2007) Evolutionary and biomedical insights from the rhesus macaque genome. Science 316:222–234PubMedCrossRefGoogle Scholar
  17. Kaizu M, Borchardt GJ, Glidden CE, Fisk DL, Loffredo JT, Watkins DI, Rehrauer WM (2007) Molecular typing of major histocompatibility complex class I alleles in the Indian rhesus macaque which restrict SIV CD8(+) T cell epitopes. Immunogenetics 59:693–703PubMedCrossRefGoogle Scholar
  18. Karl JA, Wiseman RW, Campbell KJ, Blasky AJ, Hughes AL, Ferguson B, Read DS, O’ Connor DH (2008) Identification of MHC class I sequences in Chinese-origin rhesus macaques. Immunogenetics 60:37–46PubMedCrossRefGoogle Scholar
  19. Kondo M, Kawamoto Y, Nozawa K, Matsybayashi K, Watanabe T, Griffiths O, Stanley M (1993) Population genetics of crab-eating macaques (Macaca fascicularis) on the Island of Mauritius. Am J Primatol 29:167–182CrossRefGoogle Scholar
  20. Krebs KC, Jin Z, Rudersdorf R, Hughes AL, O’ Connor DH (2005) Unusually high frequency MHC class I alleles in Mauritian origin cynomolgus macaques. J Immunol 175:5230–5239PubMedGoogle Scholar
  21. Lafont BA, Buckler-White A, Plishka R, Buckler C, Martin MA (2003) Characterization of pig-tailed macaque classical MHC class I genes: implications for MHC evolution and antigen presentation in macaques. J Immunol 171:875–885PubMedGoogle Scholar
  22. Lafont BA, McGraw CM, Stukes SA, Buckler-White A, Plishka RJ, Byrum RA, Hirsch VM, Martin MA (2007) The locus encoding an oligomorphic family of MHC-A alleles (Mane-A*06/Mamu-A*05) is present at high frequency in several macaque species. Immunogenetics 59:211–223PubMedCrossRefGoogle Scholar
  23. Lawler JV, Endy TP, Hensley LE, Garrison A, Fritz EA, Lesar M, Baric RS, Kulesh DA, Norwood DA, Wasieloski LP, Ulrich MP, Slezak TR, Vitalis E, Huggins JW, Jahrling PB, Paragas J (2006) Cynomolgus macaque as an animal model for severe acute respiratory syndrome. PLoS Med 3:677–686CrossRefGoogle Scholar
  24. Leuchte N, Berry N, Kohler B, Almond N, LeGrand R, Thorstensson R, Titti F, Sauermann U (2004) MhcDRB-sequences from cynomolgus macaques (Macaca fascicularis) of different origin. Tissue Antigens 63:529–537PubMedCrossRefGoogle Scholar
  25. Liu C, Noorchashm H, Sutter JA, Naji M, Prak EL, Boyer J, Green T, Rickels MR, Tomaszewski JE, Koeberlein B, Wang Z, Paessler ME, Velidedeoglu E, Rostami SY, Yu M, Barker CF, Naji A (2007) B lymphocyte-directed immunotherapy promotes long-term islet allograft survival in nonhuman primates. Nat Med 13:1295–1298PubMedCrossRefGoogle Scholar
  26. Loffredo JT, Friedrich TC, Leon EJ, Stephany JJ, Rodrigues DS, Spencer SP, Bean AT, Beal DR, Burwitz BJ, Rudersdorf RA, Wallace LT, Piaskowski SM, May GE, Sidney J, Gostick E, Wilson NA, Price DA, Kallas EG, Piontkivska H, Hughes AL, Sette A, Watkins DI (2007a) CD8 T cells from SIV elite controller macaques recognize mamu-B*08-Bound epitopes and select for widespread viral variation. PLoS ONE 2:1152CrossRefGoogle Scholar
  27. Loffredo JT, Maxwell J, Qi Y, Glidden CE, Borchardt GJ, Soma T, Bean AT, Beal DR, Wilson NA, Rehrauer WM, Lifson JD, Carrington M, Watkins DI (2007b) Mamu-B*08-positive macaques control simian immunodeficiency virus replication. J Virol 81:8827–8832PubMedCrossRefGoogle Scholar
  28. Loudon JE, Howells ME, Guentes A (2006) The importance of integrative anthropology: a preliminary investigation employing primatological and cultural anthropological data collection methods in assessing human-monkey co-existence in Bali, Indonesia. Ecological and Environmental Anthropology 2:2–13Google Scholar
  29. McMichael A, Hanke T (2002) The quest for an AIDS vaccine: is the CD8+ T-cell approach feasible? Nat Rev Immunol 2:283–291PubMedCrossRefGoogle Scholar
  30. Negri DR, Borghi M, Baroncelli S, Macchia I, Buffa V, Sernicola L, Leone P, Titti F, Cara A (2006) Identification of a cytotoxic T-lymphocyte (CTL) epitope recognized by Gag-specific CTLs in cynomolgus monkeys infected with simian/human immunodeficiency virus. J Gen Virol 87:3385–3392PubMedCrossRefGoogle Scholar
  31. O’Connor SL, Blasky AJ, Pendley CJ, Becker EA, Wiseman RW, Karl JA, Hughes AL, O’ Connor DH (2007) Comprehensive characterization of MHC class II haplotypes in Mauritian cynomolgus macaques. Immunogenetics 59:449–462PubMedCrossRefGoogle Scholar
  32. Otting N, Heijmans CM, Noort RC, de Groot NG, Doxiadis GG, van Rood JJ, Watkins DI, Bontrop RE (2005) Unparalleled complexity of the MHC class I region in rhesus macaques. Proc Natl Acad Sci U S A 102:1626–1631PubMedCrossRefGoogle Scholar
  33. Otting N, de Vos-Rouweler AJ, Heijmans CM, de Groot NG, Doxiadis GG, Bontrop RE (2007) MHC class I A region diversity and polymorphism in macaque species. Immunogenetics 59:367–375PubMedCrossRefGoogle Scholar
  34. Piertney SB, Oliver MK (2006) The evolutionary ecology of the major histocompatibility complex. Heredity 96:7–21PubMedGoogle Scholar
  35. Robinson J, Waller MJ, Parham P, de Groot N, Bontrop R, Kennedy LJ, Stoehr P, Marsh SG (2003) IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 31:311–314PubMedCrossRefGoogle Scholar
  36. Rozen S, Skaletsky HJ (2000) Primer3 on the WWW for general users and for biologist programmers. In S Krawetz & S Misener (eds) Bioinformatics Methods and Protocols: Methods in Molecular Biology (365–386). Totowa, NJ: Humana PressGoogle Scholar
  37. Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425PubMedGoogle Scholar
  38. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA (1999) Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283:857–860PubMedCrossRefGoogle Scholar
  39. Shively CA, Wood CE, Register TC, Willard SL, Lees CJ, Chen H, Sitruk-Ware RL, Tsong YY, Cline JM (2007) Hormone therapy effects on social behavior and activity levels of surgically postmenopausal cynomolgus monkeys. Psychoneuroendocrinology 32:981–990PubMedCrossRefGoogle Scholar
  40. Smith DG, McDonough JW, George DA (2007) Mitochondrial DNA variation within and among regional populations of longtail macaques (Macaca fascicularis) in relation to other species of the fascicularis group of macaques. Am J Primatol 69:182–198PubMedCrossRefGoogle Scholar
  41. Southwick C, Siddiqi F (1994) Population status of nonhuman primates in Asia, with emphasis on rhesus Macaques in India. Am J Primatol 34:51–59CrossRefGoogle Scholar
  42. Sussman RW, Tattersall I (1986) Distribution, abundance, and putative ecological strategy of Macaca fascicularis on the Island of Mauritius, Southwestern Indian Ocean. Folia Primatology 46:28–43CrossRefGoogle Scholar
  43. Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: Molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol Biol Evol 24:1596–1599PubMedCrossRefGoogle Scholar
  44. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882PubMedCrossRefGoogle Scholar
  45. Tosi AJ, Coke CS (2007) Comparative phylogenetics offer new insights into the biogeographic history of Macaca fascicularis and the origin of the Mauritian macaques. Mol Phylogenet Evol 42:498–504PubMedCrossRefGoogle Scholar
  46. Uda A, Tanabayashi K, Yamada YK, Akari H, Lee YJ, Mukai R, Terao K, Yamada A (2004) Detection of 14 alleles derived from the MHC class I A locus in cynomolgus monkeys. Immunogenetics 56:155–163PubMedCrossRefGoogle Scholar
  47. Uda A, Tanabayashi K, Fujita O, Hotta A, Terao K, Yamada A (2005) Identification of the MHC class I B locus in cynomolgus monkeys. Immunogenetics 57:189–197PubMedCrossRefGoogle Scholar
  48. Voris H (2000) Maps of Pleistocene sea levels in Southeast Asia: shorelines, river systems and time durations. J Biogeogr 27:1153–1167CrossRefGoogle Scholar
  49. Wang CY, Finstad CL, Walfield AM, Sia C, Sokoll KK, Chang TY, Fang XD, Hung CH, Hutter-Paier B, Windisch M (2007) Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer’s disease. Vaccine 25:3041–3052PubMedCrossRefGoogle Scholar
  50. Wiseman RW, O’ Connor DH (2007) Major histocompatibility complex-defined macaques in transplantation research. Transplant Rev 21:17–25CrossRefGoogle Scholar
  51. Wiseman RW, Wojcechowskyj JA, Greene JM, Blasky AJ, Gopon T, Soma T, Friedrich TC, O’ Connor SL, O, Connor DH (2007) Simian immunodeficiency virus SIVmac239 infection of major histocompatibility complex-identical cynomolgus macaques from Mauritius. J Virol 81:349–361PubMedCrossRefGoogle Scholar
  52. Wojcechowskyj JA, Yant LJ, Wiseman RW, O, Connor SL, O, Connor DH (2007) Control of Simian immunodeficiency virus SIVmac239 is not predicted by inheritance of Mamu-B*17-containing haplotypes. J Virol 81:406–410PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Chad J. Pendley
    • 1
  • Ericka A. Becker
    • 1
  • Julie A. Karl
    • 1
    • 2
  • Alex J. Blasky
    • 1
  • Roger W. Wiseman
    • 1
  • Austin L. Hughes
    • 3
  • Shelby L. O’Connor
    • 2
  • David H. O’Connor
    • 1
    • 2
    • 4
  1. 1.Wisconsin National Primate Research Center, University of Wisconsin—MadisonMadisonUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of Wisconsin—MadisonMadisonUSA
  3. 3.Department of Biological SciencesUniversity of South CarolinaColumbiaUSA
  4. 4.University of Wisconsin—MadisonMadisonUSA

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