Influence of the MHC genotype on the progression of experimental SIV infection in the Mauritian cynomolgus macaque
- 228 Downloads
Experimental infection of Mauritian cynomolgus macaques by simian immunodeficiency virus is a representative model of HIV infection, currently in favour for evaluating the efficacy of new preventive or curative treatments. Extensive studies of major histocompatibility complex (MHC) polymorphism by microsatellites revealed seven haplotypes (H1–H7). We present statistical evidence of the influence of MHC polymorphism on the set-point plasma viral load (PVL). Our analysis was based on the study of 45 Mauritian cynomolgus macaques inoculated by intravenous or intrarectal injection of a 50 AID50 dose of the SIVmac251 virus. The animals received no treatment before or after the inoculation. MHC polymorphism was investigated by means of 20 microsatellites distributed across the MHC and by DRB genotyping using the DGGE sequencing method. Statistical analysis with Unphased software revealed that two markers located in the class IB region significantly influenced the Log PVL and that three class IB haplotypes were significantly associated with lower (H2 or H6) or higher (H4) set-point Log PVL values. Although the impact of MHC on Log PVL was found to be low (around one Log10), it is important to dispose of animals paired for their MHC genotypes, each animal tested for a given treatment and its untreated control, to minimize the influence of the MHC and clearly reveal the effect of the treatment.
KeywordsSIVmac251 MHC Microsatellites Macaca fascicularis
We are pleased to thank Béatrice Atlan, Audrey Dauba, Stéphanie Despiau-Schiavinato and Sylvie Hébrard, Benoit Delache and Patricia Brochard for their excellent technical assistance. We thank Takashi Shiina for the location of the markers on the cynomolgus MHC map. We thank also Christophe Joubert and the animal facility staff of the CEA. We thank the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS) for its financial support.
Conflict of interest
The authors declare that they have no conflict of interest.
- Budde ML, Wiseman RW, Karl JA, Hanczaruk B, Simen BB, O’Connor DH (2010) Characterization of Mauritian cynomolgus macaque major histocompatibility complex class I haplotypes by high-resolution pyrosequencing. Immunogenetics 62(11–12):773–780. doi: 10.1007/s00251-010-0481-9 PubMedCrossRefGoogle Scholar
- Cafaro A, Bellino S, Titti F, Maggiorella MT, Sernicola L, Wiseman RW, Venzon D, Karl JA, O’Connor D, Monini P, Robert-Guroff M, Ensoli B (2010) Impact of viral dose and major histocompatibility complex class IB haplotype on viral outcome in Mauritian cynomolgus monkeys vaccinated with Tat upon challenge with simian/human immunodeficiency virus SHIV89.6P. J Virol 84:8953–8958PubMedCrossRefGoogle Scholar
- Fellay J, Ge D, Shianna KV, Colombo S, Ledergerber B, Cirulli ET, Urban TJ, Zhang K, Gumbs CE, Smith JP, Castagna A, Cozzi-Lepri A, De Luca A, Easterbrook P, Gunthard HF, Mallal S, Mussini C, Dalmau J, Martinez-Picado J, Miro JM, Obel N, Wolinsky SM, Martinson JJ, Detels R, Margolick JB, Jacobson LP, Descombes P, Antonarakis SE, Beckmann JS, O’Brien SJ, Letvin NL, McMichael AJ, Haynes BF, Carrington M, Feng S, Telenti A, Goldstein DB (2009) Common genetic variation and the control of HIV-1 in humans. PLoS Genet 5:e1000791PubMedCrossRefGoogle Scholar
- Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, Zhang K, Gumbs C, Castagna A, Cossarizza A, Cozzi-Lepri A, De Luca A, Easterbrook P, Francioli P, Mallal S, Martinez-Picado J, Miro JM, Obel N, Smith JP, Wyniger J, Descombes P, Antonarakis SE, Letvin NL, McMichael AJ, Haynes BF, Telenti A, Goldstein DB (2007) A whole-genome association study of major determinants for host control of HIV-1. Science 317:944–947PubMedCrossRefGoogle Scholar
- Florese RH, Wiseman RW, Venzon D, Karl JA, Demberg T, Larsen K, Flanary L, Kalyanaraman VS, Pal R, Titti F, Patterson LJ, Heath MJ, O’Connor DH, 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 SHIV(89.6P) infection. Vaccine 26:3312–3321PubMedCrossRefGoogle Scholar
- Giraldo-Vela JP, Rudersdorf R, Chung C, Qi Y, Wallace LT, Bimber B, Borchardt GJ, Fisk DL, Glidden CE, Loffredo JT, Piaskowski SM, Furlott JR, Morales-Martinez JP, Wilson NA, Rehrauer WM, Lifson JD, Carrington M, Watkins DI (2008) The major histocompatibility complex class II alleles Mamu-DRB1*1003 and -DRB1*0306 are enriched in a cohort of simian immunodeficiency virus-infected rhesus macaque elite controllers. J Virol 82:859–870PubMedCrossRefGoogle Scholar
- Houghton P (1988) Virus-free African cynomolgus macaques. Lab Animal 70:36–40Google Scholar
- Loffredo JT, Bean AT, Beal DR, Leon EJ, May GE, Piaskowski SM, Furlott JR, Reed J, Musani SK, Rakasz EG, Friedrich TC, Wilson NA, Allison DB, Watkins DI (2008) Patterns of CD8+ immunodominance may influence the ability of Mamu-B*08-positive macaques to naturally control simian immunodeficiency virus SIVmac239 replication. J Virol 82:1723–1738PubMedCrossRefGoogle Scholar
- Maness NJ, Yant LJ, Chung C, Loffredo JT, Friedrich TC, Piaskowski SM, Furlott J, May GE, Soma T, Leon EJ, Wilson NA, Piontkivska H, Hughes AL, Sidney J, Sette A, Watkins DI (2008) Comprehensive immunological evaluation reveals surprisingly few differences between elite controller and progressor Mamu-B*17-positive simian immunodeficiency virus-infected rhesus macaques. J Virol 82:5245–5254PubMedCrossRefGoogle Scholar
- Mee ET, Badhan A, Karl JA, Wiseman RW, Cutler K, Knapp LA, Almond N, O’Connor DH, Rose NJ (2009a) MHC haplotype frequencies in a UK breeding colony of Mauritian cynomolgus macaques mirror those found in a distinct population from the same geographic origin. J Med Primatol 38:1–14PubMedCrossRefGoogle Scholar
- Mee ET, Berry N, Ham C, Sauermann U, Maggiorella MT, Martinon F, Verschoor EJ, Heeney JL, Le Grand R, Titti F, Almond N, Rose NJ (2009b) Mhc haplotype H6 is associated with sustained control of SIVmac251 infection in Mauritian cynomolgus macaques. Immunogenetics 61:327–339PubMedCrossRefGoogle Scholar
- O’Connor DH, Mothe BR, Weinfurter JT, Fuenger S, Rehrauer WM, Jing P, Rudersdorf RR, Liebl ME, Krebs K, Vasquez J, Dodds E, Loffredo J, Martin S, McDermott AB, Allen TM, Wang C, Doxiadis GG, Montefiori DC, Hughes A, Burton DR, Allison DB, Wolinsky SM, Bontrop R, Picker LJ, Watkins DI (2003) 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 77:9029–9040PubMedCrossRefGoogle Scholar
- Sauermann U, Siddiqui R, Suh YS, Platzer M, Leuchte N, Meyer H, Matz-Rensing K, Stoiber H, Nurnberg P, Hunsmann G, Stahl-Hennig C, Krawczak M (2008) Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques. Genes Immun 9:69–80PubMedCrossRefGoogle Scholar
- Sauermann U, Stahl-Hennig C, Stolte N, Muhl T, Krawczak M, Spring M, Fuchs D, Kaup FJ, Hunsmann G, Sopper S (2000) 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 182:716–724PubMedCrossRefGoogle Scholar
- Watanabe A, Shiina T, Shimizu S, Hosomichi K, Yanagiya K, Kita YF, Kimura T, Soeda E, Torii R, Ogasawara K, Kulski JK, Inoko H (2007) A BAC-based contig map of the cynomolgus macaque (Macaca fascicularis) major histocompatibility complex genomic region. Genomics 89:402–412PubMedCrossRefGoogle Scholar
- Yant LJ, Friedrich TC, Johnson RC, May GE, Maness NJ, Enz AM, Lifson JD, O’Connor DH, Carrington M, Watkins DI (2006) The high-frequency major histocompatibility complex class I allele Mamu-B*17 is associated with control of simian immunodeficiency virus SIVmac239 replication. J Virol 80:5074–5077PubMedCrossRefGoogle Scholar