Abstract
CD4 is the major receptor on T helper cells involved in the uptake of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) into their host cells. Evolutionary studies of CD4 in primates revealed signatures of positive selection in the D1 domain that interacts with primate exogenous lentivirus gp120 proteins. Here, we studied the evolution of CD4 in lagomorphs by comparing sequences obtained for the genera Oryctolagus, Sylvilagus, Lepus, and Ochotona. Our results reveal an overall higher divergence in lagomorphs compared to primates with highest divergence in the D2 domain. A detailed analysis of a small fragment of 33 nucleotides coding for amino acids 169 to 179 in the D2 domain showed dramatic amino acid alterations with a dN/dS value of 3.2 for lagomorphs, suggesting that CD4 is under strong positive selection in this particular region. Within each leporid genus, no significant amino acid changes were observed for the D2 domain which indicates that the genetic differentiation occurred in the ancestor of each genus before the species radiation. The rabbit endogenous lentivirus type K (RELIK) found in leporids shares high structural similarity with HIV which suggests a possible interaction between RELIK and CD4. The presence of RELIK in the studied leporids, the high structural similarity to modern-day exogenous lentiviruses and the absence of exogenous lentiviruses in leporids, allows us to hypothesize that this endogenous retrovirus, that was most probably exogenous in the past, drove the divergent evolution of leporid CD4.
This is a preview of subscription content, log in via an institution to check access.
References
Abrantes J, Esteves PJ, Carmo CR, Muller A, Thompson G, van der Loo W (2008) Genetic characterization of the chemokine receptor CXCR4 gene in lagomorphs: comparison between the families Ochotonidae and Leporidae. Int J Immunogenet 35:111–117. doi:10.1111/j.1744-313X.2007.00735.x
Abrantes J, Carmo CR, Matthee CA, Yamada F, van der Loo W, Esteves PJ (2011) A shared unusual genetic change at the chemokine receptor type 5 between Oryctolagus. Bunolagus and Pentalagus. Conserv Genet 12:325–330. doi:10.1007/s10592-009-9990-1
Berger EA, Murphy PM, Farber JM (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 17:657–700. doi:10.1146/annurev.immunol.17.1.657
Carmo CR, Esteves PJ, Ferrand N, van der Loo W (2006) Genetic variation at chemokine receptor CCR5 in leporids: alteration at the 2nd extracellular domain by gene conversion with CCR2 in Oryctolagus, but not in Sylvilagus and Lepus species. Immunogenetics 58:494–501. doi:10.1007/s00251-006-0095-4
Doyle C, Strominger JL (1987) Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature 330:256–259. doi:10.1038/330256a0
Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32:1792–1797. doi:10.1093/nar/gkh340
Gouy de Bellocq J, Suchentrunk F, Baird SJ, Schaschl H (2009) Evolutionary history of an MHC gene in two leporid species: characterisation of Mhc-DQA in the European brown hare and comparison with the European rabbit. Immunogenetics 61:131–144. doi:10.1007/s00251-008-0349-4
Hall TA (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symp Ser 41:95–98
Hotzel I (2008) Conservation of inner domain modules in the surface envelope glycoproteins of an ancient rabbit lentivirus and extant lentiviruses and betaretroviruses. Virology 372:201–207. doi:10.1016/j.virol.2007.10.038
Katzourakis A, Tristem M, Pybus OG, Gifford RJ (2007) Discovery and analysis of the first endogenous lentivirus. Proc Natl Acad Sci U S A 104:6261–6265. doi:10.1073/pnas.0700471104
Keckesova Z, Ylinen LM, Towers GJ, Gifford RJ, Katzourakis A (2009) Identification of a RELIK orthologue in the European hare (Lepus europaeus) reveals a minimum age of 12 million years for the lagomorph lentiviruses. Virology 384:7–11. doi:10.1016/j.virol.2008.10.045
Larruskain A, Jugo BM (2013) Retroviral infections in sheep and goats: small ruminant lentiviruses and host interaction. Viruses 5:2043–2061. doi:10.3390/v5082043
Librado P, Rozas J (2009) DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25:1451–1452. doi:10.1093/bioinformatics/btp187
Magalhães V, Abrantes J, Munõz-Pajares AJ, Esteves PJ (2015) Genetic diversity comparison of the DQA gene in European rabbit (Oryctolagus cuniculus) populations. Immunogenetics 67(10):579–90
Matthee CA, van Vuuren BJ, Bell D, Robinson TJ (2004) A molecular supermatrix of the rabbits and hares (Leporidae) allows for the identification of five intercontinental exchanges during the Miocene. Syst Biol 53:433–447
Meyerson NR, Rowley PA, Swan CH, Le DT, Wilkerson GK, Sawyer SL (2014) Positive selection of primate genes that promote HIV-1 replication. Virology 454–455:291–298. doi:10.1016/j.virol.2014.02.029
Miller RJ, Cairns JS, Bridges S, Sarver N (2000) Human immunodeficiency virus and AIDS: insights from animal lentiviruses. J Virol 74:7187–7195
Nei M, Gojobori T (1986) Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3:418–426
Pinheiro A, de Mera IG, Alves PC, Gortazar C, de la Fuente J, Esteves PJ (2013) Sequencing of modern Lepus VDJ genes shows that the usage of VHn genes has been retained in both Oryctolagus and Lepus that diverged 12 million years ago. Immunogenetics 65:777–784. doi:10.1007/s00251-013-0728-3
Pinheiro A, Neves F, Lemos de Matos A, Abrantes J, van der Loo W, Mage R, Esteves PJ (2016) An overview of the lagomorph immune system and its genetic diversity. Immunogenetics. doi:10.1007/s00251-015-0868-8
Shimojima M et al (2004) Use of CD134 as a primary receptor by the feline immunodeficiency virus. Science 303:1192–1195. doi:10.1126/science.1092124
Surridge AK, van der Loo W, Abrantes J, Carneiro M, Hewitt GM, Esteves PJ (2008) Diversity and evolutionary history of the MHC DQA gene in leporids. Immunogenetics 60:515–525. doi:10.1007/s00251-008-0309-z
Tamura K, Stecher G, Peterson D, Filipski A, Kumar S (2013) MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol 30:2725–2729. doi:10.1093/molbev/mst197
van der Loo W, Abrantes J, Esteves PJ (2009) Sharing of endogenous lentiviral gene fragments among leporid lineages separated for more than 12 million years. J Virol 83:2386–2388. doi:10.1128/Jvi.01116-08
Wang JH et al (2001) Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule. Proc Natl Acad Sci U S A 98:10799–10804. doi:10.1073/pnas.191124098
Zhang B, Jin S, Jin J, Li F, Montelaro RC (2005) A tumor necrosis factor receptor family protein serves as a cellular receptor for the macrophage-tropic equine lentivirus. Proc Natl Acad Sci U S A 102:9918–9923. doi:10.1073/pnas.0501560102
Zhang ZD, Weinstock G, Gerstein M (2008) Rapid evolution by positive Darwinian selection in T-cell antigen CD4 in primates. J Mol Evol 66:446–456. doi:10.1007/s00239-008-9097-1
Acknowledgments
The FCT—Foundation for Science and Technology—supported the doctoral grants of Patricia de Sousa-Pereira (ref.: PD/BD/52602/2014) and the FCT Investigator grant of Joana Abrantes (ref.: IF/01396/2013). H-M.B. was supported by the programme ‘Frankfurter Forschungsförderung (FFF)’ by the Faculty of Medicine of the Johann Wolfgang von Goethe University, Frankfurt.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
de Sousa-Pereira, P., Abrantes, J., Baldauf, HM. et al. Evolutionary study of leporid CD4 reveals a hotspot of genetic variability within the D2 domain. Immunogenetics 68, 477–482 (2016). https://doi.org/10.1007/s00251-016-0909-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-016-0909-y