Quantitative Biology

, Volume 5, Issue 2, pp 173–182 | Cite as

A systematic analysis of intrinsic regulators for HIV-1 R5 to X4 phenotypic switch

  • Wei Yu
  • Yu Wu
Research Article



Human immunodeficiency virus isolates most often use chemokine receptor CCR5 or CXCR4 as a co-receptor to enter target cells. During early stages of HIV-1 infection, CCR5-tropic viruses are the predominant species. The CXCR4-tropic viruses may emerge late in infection. Recognition of factors influencing this phenotypic switch may give some hints on the antiviral strategies like anti-HIV/AIDS drugs, gene therapy and vaccines.


To investigate the mechanism that triggers R5 to X4 phenotypic switch, we performed a systematic sensitivity analysis based on a five-dimensional model with time-varying parameters. We studied the sensitivity of each factor to the CCR5-to-CXCR4 tropism switch and acquired some interesting outcomes beyond expectation.


The death rate of free virus (dV), rate that uninfected CD4+ Tcells arise from precursors (s) and proliferate as stimulated by antigens (r), and in vivo viral burst size (N) are four robust factors which are constantly observed to have a strong correlation with the evolution of viral phenotype for most patients longitudinally.


Crucial factors, which are essential to phenotypic switch and disease progression, are almost the same for different patients at different time points, including the production of both virus and CD4+ Tcells and the decay of virion. It is also worth mentioning that although the sequence of factors sorted by the influence varies between patients, the trends of influences engendered by most factors as disease progresses are similar inter-patients.


HIV-1 R5-to-X4 switch two-strain model population dynamics sensitivity analysis 



We acknowledge the supports from the National Natural Science Foundation of China (Nos. 11402227, 11621062 and 11432012), the Fundamental Research Funds for the Central Universities of China (No. 2015QNA4034), and the Thousand Young Talents Program of China.

Supplementary material

40484_2017_107_MOESM1_ESM.pdf (2 mb)
A Systematic Analysis of Intrinsic Regulators for HIV-1 R5 to X4 Phenotypic Switch


  1. 1.
    Pastore, C., Ramos, A. and Mosier, D. E. (2004) Intrinsic obstacles to human immunodeficiency virus type 1 coreceptor switching. J. Virol., 78, 7565–7574CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Koot, M., Keet, I. P. M., Vos, A. H. V., de Goede, R. E. Y., Roos, M. T. L., Coutinho, R. A., Miedema, F., Schellekens, P. T. A. and Tersmette, M. (1993) Prognostic value of HIV-1 syncytiuminducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann. Intern. Med., 118, 681–688CrossRefPubMedGoogle Scholar
  3. 3.
    Ribeiro, R. M., Hazenberg, M. D., Perelson, A. S. and Davenport, M. P. (2006) Naïve and memory cell turnover as drivers of CCR5-to-CXCR4 tropism switch in human immunodeficiency virus type 1: implications for therapy. J. Virol., 80, 802–809CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Swanstrom, R. and Coffin, J. (2012) HIV-1 pathogenesis: the virus. Cold Spring Harb. Perspect. Med., 2, a007443CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sede, M. M., Moretti, F. A., Laufer, N. L., Jones, L. R. and Quarleri, J. F. (2014) HIV-1 tropism dynamics and phylogenetic analysis from longitudinal ultra-deep sequencing data of CCR5- and CXCR4-using variants. PLoS One, 9, e102857CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Sguanci, L., Bagnoli, F. and Liò, P. (2007) Modeling HIV quasispecies evolutionary dynamics. BMC Evol. Biol., 7, S5CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Moore, J. P., Kitchen, S. G., Pugach, P. and Zack, J. A. (2004) The CCR5 and CXCR4 coreceptors—central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res. Hum. Retroviruses, 20, 111–126CrossRefPubMedGoogle Scholar
  8. 8.
    van Rij, R. P., Hazenberg, M. D., van Benthem, B. H. B., Otto, S. A., Prins, M., Miedema, F. and Schuitemaker, H. (2003) Early viral load and CD4+ T cell count, but not percentage of CCR5+ or CXCR4+ CD4+ T cells, are associated with R5-to-X4 HIV type 1 virus evolution. AIDS Res. Hum. Retroviruses, 19, 389–398CrossRefPubMedGoogle Scholar
  9. 9.
    Boyd, M. T., Simpson, G. R., Cann, A. J., Johnson, M. A. and Weiss, R. A. (1993) A single amino acid substitution in the V1 loop of human immunodeficiency virus type 1 gp120 alters cellular tropism. J. Virol., 67, 3649–3652PubMedPubMedCentralGoogle Scholar
  10. 10.
    Cocchi, F., DeVico, A. L., Garzino-Demo, A., Cara, A., Gallo, R. C. and Lusso, P. (1996) The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. Nat. Med., 2, 1244–1247CrossRefPubMedGoogle Scholar
  11. 11.
    Fouchier, R. A. M., Groenink, M., Kootstra, N. A., Tersmette, M., Huisman, H. G., Miedema, F. and Schuitemaker, H. (1992) Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J. Virol., 66, 3183–3187PubMedPubMedCentralGoogle Scholar
  12. 12.
    De Jong, J. J., De Ronde, A., Keulen, W., Tersmette, M. and Goudsmit, J. (1992) Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype: analysis by single amino acid substitution. J. Virol., 66, 6777–6780PubMedPubMedCentralGoogle Scholar
  13. 13.
    McKnight, A. and Clapham, P. R. (1995) Immune escape and tropism of HIV. Trends Microbiol., 3, 356–361CrossRefPubMedGoogle Scholar
  14. 14.
    Eckstein, D. A., Penn, M. L., Korin, Y. D., Scripture-Adams, D. D., Zack, J. A., Kreisberg, J. F., Roederer, M., Sherman, M. P., Chin, P. S. and Goldsmith, M. A. (2001) HIV-1 actively replicates in naive CD4+ T cells residing within human lymphoid tissues. Immunity, 15, 671–682CrossRefPubMedGoogle Scholar
  15. 15.
    Trouplin, V., Salvatori, F., Cappello, F., Obry, V., Brelot, A., Heveker, N., Alizon, M., Scarlatti, G., Clavel, F. and Mammano, F. (2001) Determination of coreceptor usage of human immuno-deficiency virus type 1 from patient plasma samples by using a recombinant phenotypic assay. J. Virol., 75, 251–259CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Connor, R. I., Sheridan, K. E., Ceradini, D., Choe, S. and Landau, N. R. (1997) Change in coreceptor use correlates with disease progression in HIV-1–infected individuals. J. Exp. Med., 185, 621–628CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    van’ t Wout, A. B., Blaak, H., Ran, L. J., Brouwer, M., Kuiken, C. and Schuitemaker, H. (1998) Evolution of syncytium-inducing and non-syncytium-inducing biological virus clones in relation to replication kinetics during the course of human immunodeficiency virus type 1 infection. J. Virol., 72, 5099–5107Google Scholar
  18. 18.
    Verhofstede, C., Nijhuis, M. and Vandekerckhove, L. (2012) Correlation of coreceptor usage and disease progression. Curr. Opin. HIV AIDS, 7, 432–439CrossRefPubMedGoogle Scholar
  19. 19.
    Regoes, R. R. and Bonhoeffer, S. (2005) The HIV coreceptor switch: a population dynamical perspective. Trends Microbiol., 13, 269–277CrossRefPubMedGoogle Scholar
  20. 20.
    Tersmette, M. and Miedema, F. (1990) Interactions between HIV and the host immune system in the pathogenesis of AIDS. AIDS, 4, S57–S66CrossRefPubMedGoogle Scholar
  21. 21.
    Miedema, F., Tersmette, M. and van Lier, R. A. W. (1990) AIDS pathogenesis: a dynamic interaction between HIV and the immune system. Immunol. Today, 11, 293–297CrossRefPubMedGoogle Scholar
  22. 22.
    Berkowitz, R. D., Alexander, S., Bare, C., Linquist-Stepps, V., Bogan, M., Moreno, M. E., Gibson, L., Wieder, E. D., Kosek, J., Stoddart, C. A., et al. (1998) CCR5- and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo. J. Virol., 72, 10108–10117PubMedPubMedCentralGoogle Scholar
  23. 23.
    Le, A. Q., Taylor, J., Dong, W., McCloskey, R., Woods, C., Danroth, R., Hayashi, K., Milloy, M. J., Poon, A. F. Y. and Brumme, Z. L. (2015) Differential evolution of a CXCR4-using HIV-1 strain in CCR5wt/wt and CCR5Δ32/Δ32 hosts revealed by longitudinal deep sequencing and phylogenetic reconstruction. Sci. Rep., 5, 17607CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Regoes, R. and Bonhoeffer, S. (2002) HIV coreceptor usage and drug treatment. J. Theor. Biol., 217, 443–457CrossRefPubMedGoogle Scholar
  25. 25.
    Perelson, A. S., Kirschner, D. E. and De Boer, R. (1993) Dynamics of HIV infection of CD4+ T cells. Math. Biosci., 114, 81–125CrossRefPubMedGoogle Scholar
  26. 26.
    Perelson, A. S. and Nelson, P.W. (1999) Mathematical analysis of HIV-1 dynamics in vivo. SIAM Rev., 41, 3–44CrossRefGoogle Scholar
  27. 27.
    Phillips, A. N. (1996) Reduction of HIV concentration during acute infection: independence from a specific immune response. Science, 271, 497–499CrossRefPubMedGoogle Scholar
  28. 28.
    Zhang, Z., Schuler, T., Zupancic, M., Wietgrefe, S., Staskus, K. A., Reimann, K. A., Reinhart, T. A., Rogan, M., Cavert, W., Miller, C. J., et al. (1999) Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science, 286, 1353–1357CrossRefPubMedGoogle Scholar
  29. 29.
    Merrill, S. J. (1987) AIDS: Background and the dynamics of the decline of immunocompetence, pp. 59–75. In Theoretical Immunology WorkshopGoogle Scholar
  30. 30.
    Kupfer, B., Kaiser, R., Rockstroh, J. K., Matz, B. and Schneweis, K. E. (1998) Role of HIV-1 phenotype in viral pathogenesis and its relation to viral load and CD4+ T-cell count. J. Med. Virol., 56, 259–263CrossRefPubMedGoogle Scholar
  31. 31.
    Dustin, M. L. and Shaw, A. S. (1999) Costimulation: building an immunological synapse. Science, 283, 649–650CrossRefPubMedGoogle Scholar
  32. 32.
    Wilson, D. P., Mattapallil, J. J., Lay, M. D. H., Zhang, L., Roederer, M. and Davenport, M. P. (2007) Estimating the infectivity of CCR5-tropic simian immunodeficiency virus SIV (mac251) in the gut. J. Virol., 81, 8025–8029CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hellerstein, M. K., Hoh, R. A., Hanley, M. B., Cesar, D., Lee, D., Neese, R. A. and McCune, J. M. (2003) Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J. Clin. Invest., 112, 956–966CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Hazenberg, M. D., Stuart, J. W., Otto, S. A., Borleffs, J. C. C., Boucher, C. A. B., de Boer, R. J., Miedema, F. and Hamann, D. (2000) T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood, 95, 249–255PubMedGoogle Scholar
  35. 35.
    McCune, J. M., Hanley, M. B., Cesar, D., Halvorsen, R., Hoh, R., Schmidt, D., Wieder, E., Deeks, S., Siler, S., Neese, R., et al. (2000) Factors influencing T-cell turnover in HIV-1-seropositive patients. J. Clin. Invest., 105, R1–R8CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Wu, Y., Lu, Y., Chen, W., Fu, J. and Fan, R. (2012) In silico experimentation of glioma microenvironment development and anti-tumor therapy. PLoS Comput. Biol., 8, e1002355CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH 2017

Authors and Affiliations

  1. 1.Department of Engineering MechanicsZhejiang UniversityHangzhouChina
  2. 2.Key Laboratory of Soft Machines and Smart Devices of Zhejiang ProvinceZhejiang UniversityHangzhouChina
  3. 3.Soft Matter Research CenterZhejiang UniversityHangzhouChina

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