Skip to main content
NCBI home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2010 Oct 17;53(10):1204–1214. doi: 10.1007/s11427-010-4066-5

Complex positive selection pressures drive the evolution of HIV-1 with different co-receptor tropisms

ChiYu Zhang 1,✉, Na Ding 1, KePing Chen 1, RongGe Yang 2,✉
PMCID: PMC7089306  PMID: 20953943

Abstract

HIV-1 co-receptor tropism is central for understanding the transmission and pathogenesis of HIV-1 infection. We performed a genome-wide comparison between the adaptive evolution of R5 and X4 variants from HIV-1 subtypes B and C. The results showed that R5 and X4 variants experienced differential evolutionary patterns and different HIV-1 genes encountered various positive selection pressures, suggesting that complex selection pressures are driving HIV-1 evolution. Compared with other hypervariable regions of Gp120, significantly more positively selected sites were detected in the V3 region of subtype B X4 variants, V2 region of subtype B R5 variants, and V1 and V4 regions of subtype C X4 variants, indicating an association of positive selection with co-receptor recognition/binding. Intriguingly, a significantly higher proportion (33.3% and 55.6%, P<0.05) of positively selected sites were identified in the C3 region than other conserved regions of Gp120 in all the analyzed HIV-1 variants, indicating that the C3 region might be more important to HIV-1 adaptation than previously thought. Approximately half of the positively selected sites identified in the env gene were identical between R5 and X4 variants. There were three common positively selected sites (96, 113 and 281) identified in Gp41 of all X4 and R5 variants from subtypes B and C. These sites might not only suggest a functional importance in viral survival and adaptation, but also imply a potential cross-immunogenicity between HIV-1 R5 and X4 variants, which has important implications for AIDS vaccine development.

Keywords: HIV-1 co-receptor tropism, adaptive evolution, positively selected site, R5 and X4, Gp120, epitopes

Contributor Information

ChiYu Zhang, Email: zhangcy1999@hotmail.com.

RongGe Yang, Email: ryang@wh.iov.cn.

References

  • 1.Berger E. A., Murphy P. M., Farber J. M. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol. 1999;17:657–700. doi: 10.1146/annurev.immunol.17.1.657. [DOI] [PubMed] [Google Scholar]
  • 2.Regoes R. R., Bonhoeffer S. The HIV coreceptor switch: a population dynamical perspective. Trends Microbiol. 2005;13:269–277. doi: 10.1016/j.tim.2005.04.005. [DOI] [PubMed] [Google Scholar]
  • 3.Moore J. P., Kitchen S. G., Pugach P., et al. The CCR5 and CXCR4 coreceptors—central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 2004;20:111–126. doi: 10.1089/088922204322749567. [DOI] [PubMed] [Google Scholar]
  • 4.Berger E. A., Doms R. W., Fenyo E. M., et al. A new classification for HIV-1. Nature. 1998;391:240. doi: 10.1038/34571. [DOI] [PubMed] [Google Scholar]
  • 5.Bjorndal A., Deng H., Jansson M., et al. Coreceptor usage of primary human immunodeficiency virus type 1 isolates varies according to biological phenotype. J Virol. 1997;71:7478–7487. doi: 10.1128/jvi.71.10.7478-7487.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Connor R. I., Sheridan K. E., Ceradini D., et al. Change in coreceptor use correlates with disease progression in HIV-1-infected individuals. J Exp Med. 1997;185:621–628. doi: 10.1084/jem.185.4.621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Ross H. A., Rodrigo A. G. Immune-mediated positive selection drives human immunodeficiency virus type 1 molecular variation and predicts disease duration. J Virol. 2002;76:11715–11720. doi: 10.1128/JVI.76.22.11715-11720.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Choisy M., Woelk C. H., Guegan J. F., et al. Comparative study of adaptive molecular evolution in different human immunodeficiency virus groups and subtypes. J Virol. 2004;78:1962–1970. doi: 10.1128/JVI.78.4.1962-1970.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Nielsen R., Yang Z. Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics. 1998;148:929–936. doi: 10.1093/genetics/148.3.929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Yang W., Bielawski J. P., Yang Z. Widespread adaptive evolution in the human immunodeficiency virus type 1 genome. J Mol Evol. 2003;57:212–221. doi: 10.1007/s00239-003-2467-9. [DOI] [PubMed] [Google Scholar]
  • 11.Travers S. A., O’Connell M. J., McCormack G. P., et al. Evidence for heterogeneous selective pressures in the evolution of the env gene in different human immunodeficiency virus type 1 subtypes. J Virol. 2005;79:1836–1841. doi: 10.1128/JVI.79.3.1836-1841.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Zanotto P. M., Kallas E. G., de Souza R. F., et al. Genealogical evidence for positive selection in the nef gene of HIV-1. Genetics. 1999;153:1077–1089. doi: 10.1093/genetics/153.3.1077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.de Oliveira T., Salemi M., Gordon M., et al. Mapping sites of positive selection and amino acid diversification in the HIV genome: an alternative approach to vaccine design? Genetics. 2004;167:1047–1058. doi: 10.1534/genetics.103.018135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Soares A. E., Soares M. A., Schrago C. G. Positive selection on HIV accessory proteins and the analysis of molecular adaptation after interspecies transmission. J Mol Evol. 2008;66:598–604. doi: 10.1007/s00239-008-9112-6. [DOI] [PubMed] [Google Scholar]
  • 15.Carvajal-Rodriguez A., Posada D., Perez-Losada M., et al. Disease progression and evolution of the HIV-1 env gene in 24 infected infants. Infect Genet Evol. 2008;8:110–120. doi: 10.1016/j.meegid.2007.10.009. [DOI] [PubMed] [Google Scholar]
  • 16.Leal E., Janini M., Diaz R. S. Selective pressures of human immunodeficiency virus type 1 (HIV-1) during pediatric infection. Infect Genet Evol. 2007;7:694–707. doi: 10.1016/j.meegid.2007.07.008. [DOI] [PubMed] [Google Scholar]
  • 17.Williamson S. Adaptation in the env gene of HIV-1 and evolutionary theories of disease progression. Mol Biol Evol. 2003;20:1318–1325. doi: 10.1093/molbev/msg144. [DOI] [PubMed] [Google Scholar]
  • 18.Yamaguchi Y., Gojobori T. Evolutionary mechanisms and population dynamics of the third variable envelope region of HIV within single hosts. Proc Natl Acad Sci USA. 1997;94:1264–1269. doi: 10.1073/pnas.94.4.1264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Jensen M. A., Li F. S., van’t Wout A. B., et al. Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences. J Virol. 2003;77:13376–13388. doi: 10.1128/JVI.77.24.13376-13388.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Sing T., Low A. J., Beerenwinkel N., et al. Predicting HIV coreceptor usage on the basis of genetic and clinical covariates. Antivir Ther. 2007;12:1097–1106. [PubMed] [Google Scholar]
  • 21.Xu S., Huang X., Xu H., et al. Improved prediction of coreceptor usage and phenotype of HIV-1 based on combined features of V3 loop sequence using random forest. J Microbiol. 2007;45:441–446. [PubMed] [Google Scholar]
  • 22.Nozawa M., Suzuki Y., Nei M. Reliabilities of identifying positive selection by the branch-site and the site-prediction methods. Proc Natl Acad Sci USA. 2009;106:6700–6705. doi: 10.1073/pnas.0901855106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Tamura K., Dudley J., Nei M., et al. MEGA4: molecular evolutionary genetics analysis (MEGA) software version 4. 0. Mol Biol Evol. 2007;24:1596–1599. doi: 10.1093/molbev/msm092. [DOI] [PubMed] [Google Scholar]
  • 24.Guindon S., Lethiec F., Duroux P., et al. PHYML Online—a web server for fast maximum likelihood-based phylogenetic inference. Nucleic Acids Res. 2005;33:W557–W559. doi: 10.1093/nar/gki352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Yang Z. PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol. 2007;24:1586–1591. doi: 10.1093/molbev/msm088. [DOI] [PubMed] [Google Scholar]
  • 26.Yang Z., Nielsen R., Goldman N., et al. Codon-substitution models for heterogeneous selection pressure at amino acid sites. Genetics. 2000;155:431–449. doi: 10.1093/genetics/155.1.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Anisimova M., Bielawski J. P., Yang Z. Accuracy and power of the likelihood ratio test in detecting adaptive molecular evolution. Mol Biol Evol. 2001;18:1585–92. doi: 10.1093/oxfordjournals.molbev.a003945. [DOI] [PubMed] [Google Scholar]
  • 28.Anisimova M., Bielawski J. P., Yang Z. Accuracy and power of bayes prediction of amino acid sites under positive selection. Mol Biol Evol. 2002;19:950–958. doi: 10.1093/oxfordjournals.molbev.a004152. [DOI] [PubMed] [Google Scholar]
  • 29.Pond S. L., Frost S. D. Datamonkey: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics. 2005;21:2531–2533. doi: 10.1093/bioinformatics/bti320. [DOI] [PubMed] [Google Scholar]
  • 30.Hwang S. S., Boyle T. J., Lyerly H. K., et al. Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science. 1991;253:71–74. doi: 10.1126/science.1905842. [DOI] [PubMed] [Google Scholar]
  • 31.Javaherian K., Langlois A. J., LaRosa G. J., et al. Broadly neutralizing antibodies elicited by the hypervariable neutralizing determinant of HIV-1. Science. 1990;250:1590–1593. doi: 10.1126/science.1703322. [DOI] [PubMed] [Google Scholar]
  • 32.Wain L. V., Bailes E., Bibollet-Ruche F., et al. Adaptation of HIV-1 to its human host. Mol Biol Evol. 2007;24:1853–1860. doi: 10.1093/molbev/msm110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Sarafianos S. G., Das K., Tantillo C., et al. Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA. EMBO J. 2001;20:1449–1461. doi: 10.1093/emboj/20.6.1449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Parren P. W., Moore J. P., Burton D. R., et al. The neutralizing antibody response to HIV-1: viral evasion and escape from humoral immunity. AIDS. 1999;13SupplA:S137–S162. [PubMed] [Google Scholar]
  • 35.Klenerman P., Wu Y., Phillips R. HIV: current opinion in escapology. Curr Opin Microbiol. 2002;5:408–413. doi: 10.1016/S1369-5274(02)00339-9. [DOI] [PubMed] [Google Scholar]
  • 36.Fouchier R. A., Groenink M., Kootstra N. A., et al. Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J Virol. 1992;66:3183–3187. doi: 10.1128/jvi.66.5.3183-3187.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Xiao L., Owen S. M., Goldman I., et al. CCR5 coreceptor usage of non-syncytium-inducing primary HIV-1 is independent of phylogenetically distinct global HIV-1 isolates: delineation of consensus motif in the V3 domain that predicts CCR-5 usage. Virology. 1998;240:83–92. doi: 10.1006/viro.1997.8924. [DOI] [PubMed] [Google Scholar]
  • 38.Boyd M. T., Simpson G. R., Cann A. J., et al. A single amino acid substitution in the V1 loop of human immunodeficiency virus type 1 gp120 alters cellular tropism. J Virol. 1993;67:3649–3652. doi: 10.1128/jvi.67.6.3649-3652.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Smyth R. J., Yi Y., Singh A., et al. Determinants of entry cofactor utilization and tropism in a dualtropic human immunodeficiency virus type 1 primary isolate. J Virol. 1998;72:4478–4484. doi: 10.1128/jvi.72.5.4478-4484.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Groenink M., Fouchier R. A., Broersen S., et al. Relation of phenotype evolution of HIV-1 to envelope V2 configuration. Science. 1993;260:1513–1516. doi: 10.1126/science.8502996. [DOI] [PubMed] [Google Scholar]
  • 41.Pastore C., Nedellec R., Ramos A., et al. Human immunodeficiency virus type 1 coreceptor switching: V1/V2 gain-of-fitness mutations compensate for V3 loss-of-fitness mutations. J Virol. 2006;80:750–758. doi: 10.1128/JVI.80.2.750-758.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Sullivan N., Thali M., Furman C., et al. Effect of amino acid changes in the V1/V2 region of the human immunodeficiency virus type 1 gp120 glycoprotein on subunit association, syncytium formation, and recognition by a neutralizing antibody. J Virol. 1993;67:3674–3679. doi: 10.1128/jvi.67.6.3674-3679.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Ghaffari G., Tuttle D. L., Briggs D., et al. Complex determinants in human immunodeficiency virus type 1 envelope gp120 mediate CXCR4-dependent infection of macrophages. J Virol. 2005;79:13250–13261. doi: 10.1128/JVI.79.21.13250-13261.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Cho M. W., Lee M. K., Carney M. C., et al. Identification of determinants on a dualtropic human immunodeficiency virus type 1 envelope glycoprotein that confer usage of CXCR4. J Virol. 1998;72:2509–2515. doi: 10.1128/jvi.72.3.2509-2515.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Bunnik E. M., Pisas L., van Nuenen A. C., et al. Autologous neutralizing humoral immunity and evolution of the viral envelope in the course of subtype B human immunodeficiency virus type 1 infection. J Virol. 2008;82:7932–7941. doi: 10.1128/JVI.00757-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Chambers P., Pringle C. R., Easton A. J. Heptad repeat sequences are located adjacent to hydrophobic regions in several types of virus fusion glycoproteins. J Gen Virol. 1990;71:3075–3080. doi: 10.1099/0022-1317-71-12-3075. [DOI] [PubMed] [Google Scholar]
  • 47.Zhang C. Y., Wei J. F., He S. H. Adaptive evolution of the spike gene of SARS coronavirus: changes in positively selected sites in different epidemic groups. BMC Microbiol. 2006;6:88. doi: 10.1186/1471-2180-6-88. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Science China. Life Sciences are provided here courtesy of Nature Publishing Group

RESOURCES