Improved Prediction of Coreceptor Usage and Phenotype of HIV-1 Based on Combined Features of V3 Loop Sequence Using Random Forest

  • Xu, Shungao (Department of Biochemistry and Molecular Biology, Jiangsu University School of Medical Technology) ;
  • Huang, Xinxiang (Department of Biochemistry and Molecular Biology, Jiangsu University School of Medical Technology) ;
  • Xu, Huaxi (Department of Biochemistry and Molecular Biology, Jiangsu University School of Medical Technology) ;
  • Zhang, Chiyu (Department of Biochemistry and Molecular Biology, Jiangsu University School of Medical Technology)
  • Published : 2007.10.30


HIV-1 coreceptor usage and phenotype mainly determined by V3 loop are associated with the disease progression of AIDS. Predicting HIV-1 coreceptor usage and phenotype facilitates the monitoring of R5-to-X4 switch and treatment decision-making. In this study, we employed random forest to predict HIV-1 biological phenotype, based on 37 random features of V3 loop. In comparison with PSSM method, our RF predictor obtained higher prediction accuracy (95.1% for coreceptor usage and 92.1% for phenotype), especially for non-B non-C HIV-l subtypes (96.6% for coreceptor usage and 95.3% for phenotype). The net charge, polarity of V3 loop and five V3 sites are seven most important features for predicting HIV-1 coreceptor usage or phenotype. Among these features, V3 polarity and four V3 sites (22, 12, 18 and 13) are first reported to have high contribution to HIV-1 biological phenotype prediction.


  1. Berger, E.A., R.W. Doms, E.M. Fenyo, B.T. Korber, D.R. Littman, J.P. Moore, Q.J. Sattentau, H. Schuitemaker, J. Sodroski, and R.A. Weiss. 1998. A new classification for HIV-1. Nature 391, 240
  2. Bjorndal, A., H. Deng, M. Jansson, J.R. Fiore, C. Colognesi, A. Karlsson, J. Albert, G. Scarlatti, D.R. Littman, and E.M. Fenyo. 1997. Coreceptor usage of primary human immunodeficiency virus type 1 isolates varies according to biological phenotype. J. Virol. 71, 7478-7487
  3. Breiman, L. 2001. Random Forests. Mach Learn. 45, 5-32
  4. Brelot, A., N. Heveker, K. Adema, M.J. Hosie, B. Willett, and M. Alizon. 1999. Effect of mutations in the second extracellular loop of CXCR4 on its utilization by human and feline immunodeficiency viruses. J. Virol. 73, 2576-2586
  5. Briggs, D.R., D.L. Tuttle, J.W. Sleasman, and M.M. Goodenow. 2000. Envelope V3 amino acid sequence predicts HIV-1 phenotype (co-receptor usage and tropism for macrophages). AIDS 14, 2937-2939
  6. Connor, R.I., K.E. Sheridan, D. Ceradini, S. Choe, and N.R. Landau. 1997. Change in coreceptor use coreceptor use correlates with disease progression in HIV-1--infected individuals. J. Exp. Med. 185, 621-628
  7. Crooks, G.E., G. Hon, J.M. Chandonia, and S.E. Brenner. 2004. WebLogo: a sequence logo generator. Genome Res. 14, 1188-1190
  8. De Jong, J.J., A. De Ronde, W. Keulen, M. Tersmette, and J. Goudsmit. 1992. Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytiuminducing phenotype: analysis by single amino acid substitution. J. Virol. 66, 6777-6780
  9. Fouchier, R.A., M. Groenink, N.A. Kootstra, M. Tersmette, H.G. Huisman, F. Miedema, and H. Schuitemaker. 1992. Phenotypeassociated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J. Virol. 66, 3183-3187
  10. Hwang, S.S., T.J. Boyle, H.K. Lyerly, and B.R. Cullen. 1991. Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science 253, 71-74
  11. Jensen, M.A., M. Coetzer, A.B. Van't Wout, L. Morris, and J.I. Mullins. 2006. A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on envelope V3 sequences. J. Virol. 80, 4698-4704
  12. Jensen, M.A., F.S. Li, A.B. Van't Wout, D.C. Nickle, D. Shriner, H.X. He, S. McLaughlin, R. Shankarappa, J.B. Margolick, and J.I. Mullins. 2003. 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. 77, 13376-13388
  13. Jensen, M.A. and A.B. Van't Wout. 2003. Predicting HIV-1 coreceptor usage with sequence analysis. AIDS Rev. 5, 104-112
  14. Kawashima, S., H. Ogata, and M. Kanehisa. 1999. AAindex: Amino Acid Index Database. Nucleic Acids Res. 27, 368-369
  15. Milich, L., B.H. Margolin, and R. Swanstrom. 1997. Patterns of amino acid variability in NSI-like and SI-like V3 sequences and a linked change in the CD4-binding domain of the HIV-1 Env protein. Virology 239, 108-118
  16. Pillai, S., B. Good, D. Richman, and J. Corbeil. 2003. A new perspective on V3 phenotype prediction. AIDS Res. Hum. Retroviruses 19, 145-149
  17. Resch, W., N. Hoffman, and R. Swanstrom. 2001. Improved success of phenotype prediction of the human immunodeficiency virus type 1 from envelope variable loop 3 sequence using neural networks. Virology 288, 51-62
  18. Richman, D.D. and S.A. Bozzette. 1994. The impact of the syncytium- inducing phenotype of human immunodeficiency virus on disease progression. J. Infect Dis. 169, 968-974
  19. Shioda, T., J.A. Levy, and C. Cheng-Mayer. 1991. Macrophage and T cell-line tropisms of HIV-1 are determined by specific regions of the envelope gp120 gene. Nature 349, 167-169
  20. Svetnik, V., A. Liaw, C. Tong, J.C. Culberson, R.P. Sheridan, and B.P. Feuston. 2003. Random forest: a classification and regression tool for compound classification and QSAR modeling. J. Chem. Inf. Comput. Sci. 43, 1947-1958
  21. Tersmette, M., R.E. De Goede, B.J. Al, I.N. Winkel, R.A. Gruters, H.T. Cuypers, H.G. Huisman, and F. Miedema. 1988. Differential syncytium-inducing capacity of human immunodeficiency virus isolates: frequent detection of syncytium-inducing isolates in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. J. Virol. 62, 2026-2032
  22. Thompson, J.D., T.J. Gibson, F. Plewniak, F. Jeanmougin, and D.G. Higgins. 1997. The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 25, 4876-4882
  23. Xiao, L., S.M. Owen, I. Goldman, A.A. Lal, J.J. deJong, J. Goudsmit, and R.B. Lal. 1998. 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 240, 83-92