Abstract
In this paper, we show how a game theoretic analysis can provide a model to explain the interdependence of host produced APOBEC3G levels and virus encoded Vif levels. We then use the relationship between these two opposing proteins in order to predict the success of two different HIV-1 viral variants, R5 and X4. From our analysis, we show that when APOBEC3G strongly favors mutation from an R5 strain to an X4 strain, it can be optimal for HIV-1 to suppress transmission of the X4 variant, despite the loss of X4 fitness potential. This is particularly true when the X4 strain significantly interferes with the host adaptive immune response, when Vif production is limited, or when host APOBEC3G targets the X4 strain more severely than the R5 strain. Using the proposed game theoretic analysis, we show that transmitting only R5 viruses has two advantages so far as HIV-1 is concerned. First, it allows for an increased R5 viral load due to immune interference caused by the X4 strain, and second, it forces the host to down-regulate APOBEC3G production, which is automatically favorable to the virus. APOBEC3G down-regulation, which is predicted in our model for a wide range of parameter values, may offer an explanation for the observed low level of APOBEC3G transcription and translation in hosts infected with HIV-1.
Similar content being viewed by others
References
Berkhout, B., & de Ronde, A. (2004). APOBEC3G versus reverse transcriptase in the generation of HIV-1 drug-resistance mutation. AIDS, 18, 1861–1863.
Berkowitz, R. D., Alexander, S., Bare, C., Lindquist-Stepps, V., Bogan, M., Moreno, M. E., Gibson, L., Wieder, E., Kosek, J., Stoddart, C. A., & McCune, J. M. (1998). CCR5- and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo. J. Virol., 72, 10108–10117.
Biebricher, C. K., & Eigen, M. (2005). The error threshold. Virus Res., 107, 117–127.
Bjorndal, A., Deng, H., Jansson, M., Fiore, J., Colognesi, C., Karlsson, A., Albert, J., Scarlatti, G., Littman, D., & Fenyö, E. (1997). Coreceptor usage of primary human immunodeficiency virus type 1 isolates varies according to biological phenotype. J. Virol., 71, 7478–7487.
Bozzette, S., McCutchan, J., Spector, S., Wright, B., & Richman, D. (1993). A cross-sectional comparison of persons with syncytium- and non-syncytium-inducing human immunodeficiency virus. J. Infect. Dis., 168, 1374–1379.
Bremermann, H. J., & Pickering, J. (1983). A game-theoretical model of parasite virulence. J. Theor. Biol., 100, 411–426.
Callaway, D. S., Ribeiro, R. M., & Nowak, M. A. (1999). Virus phenotype switching and disease progression in HIV-1 infection. Proc. R. Soc. Lond. B Biol. Sci., 266, 2523–2530.
Chao, L., Davenport, M. P., Forrest, S., & Perelson, A. S. (2004). A stochastic model of cytotoxic T-cell responses. J. Theor. Biol., 228, 227–240.
Cho, S.-J., Drechsler, H., Burke, R., Arens, M., Powderly, W., & Davidson, N. (2006). APOBEC3F and APOBEC3G mRNA levels do not correlate with human immunodeficiency virus type 1 plasma viremia or CD4+ T-cell count. J. Virol., 80, 2069–2072.
Connor, R., Mohri, H., Cao, Y., & Ho, D. (1993). Increased viral burden and cytopathicity correlate temporally with CD4+ T-lymphocyte decline and clinical progression in human immunodeficiency virus type 1-infected individuals. J. Virol., 67, 1772–1777.
Connor, R., Sheridan, K., Ceradini, D., Choe, S., & Landau, N. (1997). Change in coreceptor use correlates with disease progression in HIV-1 infected individuals. J. Exp. Med., 185, 621–628.
Coombs, D., Gilchrist, M., & Ball, C. (2007). Evaluating the importance of within- and between-host selection pressures on the evolution of chronic pathogens. Theor. Popul. Biol., 72, 576–591.
Doms, R. W., & Trono, D. (2000). The plasma membrane as a combat zone in the HIV battlefield. Genes Dev., 14, 2677–2688.
Fouchier, R., Mayaard, M., Brouwer, M., Hovenkamp, E., & Schuitemaker, H. (1996). Broader tropism and higher cytopathicity for CD4+ T-cells of a syncytium-inducing compared to a non-syncytium-inducing HIV-1 isolate as a mechanism for accelerated CD4+ T-cell decline in vivo. Virology, 219, 87–96.
Gilchrist, M., & Coombs, D. (2006). Evolution of virulence: interdependence, constraints, and selection using nested models. Theor. Popul. Biol., 69, 145–153.
Groenink, M., Fouchier, R., de Goede, R., de Wolf, F., Gruters, R., Cuypers, H., Huisman, H., & Tersmette, M. (1991). Phenotypical heterogeneity in a panel of infectious molecular human immunodeficiency virus type 1 clones derived from a single individual. J. Virol., 65, 1968–1975.
Ho, D., Neumann, A. U., Perelson, A. S., Chen, W., Leonard, J. M., & Markowitz, M. (1995). Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature, 373, 123–126.
Ho, S., Silvana, T., Shek, L., Li, A., Gettie, A., Blanchard, J., Boden, D., & Cheng-Mayer, C. (2007). Coreceptor switch in R5-tropic simian/human immunodeficiency virus-infected macaques. J. Virol., 81, 8621–8633.
Komohara, Y., Yano, H., Schichijo, S., Shimotohno, K., Itoh, K., & Yamada, A. (2006). High expression of APOBEC3G in patients infected with hepatitis C virus. J. Mol. Histol., 37, 327–332.
Koot, M., Keet, I., Vos, A., de Goede, R., Roos, M., Coutinho, R., Miedema, F., Schellekens, P., & Tersmette, M. (1993). Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression of AIDS. Ann. Intern. Med., 118, 681–688.
LeGuern, M., Shioda, T., Levy, J., & Cheng-Mayer, C. (1993). Single amino acid change in Tat determines the different rates of replication of two sequential HIV-1 isolates. Virology, 195, 441–447.
Long, E., Rainwater, S., Lavreys, L., Mandaliya, K., & Overbaugh, J. (2002). HIV type 1 variants transmitted to women in Kenya require the CCR5 coreceptor for entry, regardless of the genetic complexity of the infecting virus. AIDS Res. Hum. Retrovir., 18, 567–576.
Nowak, M., & May, R. (2000). Virus dynamics: mathematical principles of immunology and virology. London: Oxford University Press.
Panos, G., & Nelson, M. (2007). HIV-1 tropism. Biomark. Med., 1, 473–481.
Pastore, C., Ramos, A., & Mosier, D. (2004). Intrinsic obstacles to human immunodeficiency virus type 1 coreceptor switching. J. Virol., 78, 7565–7574.
Perelson, A. S., Neumann, A. U., Markowitz, M., Leonard, J. M. D., & Ho, D. (1996). HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science, 271, 1582–1586.
Pillai, S., Wong, J., & Barbour, J. (2008). Turning up the volume on mutational pressure: is more of a good thing always better? Retrovirology, 5, 26.
Pope, M., & Haase, A. (2003). Transmission, acute HIV-1 infection and the quest for strategies to prevent infection. Nat. Med., 9, 847–852.
Ribeiro, M. R., Hazenberg, D. M., Perelson, A. S., & Davenport, P. M. (2006). Naive and memory cell turnover as drivers of CCR5-to-CXCR4 tropism switch in human immunodeficiency virus type 1: implications for therapy. J. Virol., 80, 802–809.
Richman, D. D., & Bozzette, S. A. (1994). The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J. Infect. Dis., 169, 968–974.
Schmidtmayerova, H., Alfano, M., Nuovo, G., & Bukrinsky, M. (1998). Human immunodeficiency virus type 1 T-lymphotropic strains enter macrophages via a CD4- and CXCR4-mediated pathway: replication is restricted at a postentry level. J. Virol., 72, 4633–4642.
Schuitemaker, H., Koot, M., Kootstra, N., Dercksen, M., Goede, R., Steenwijk, R., Lange, J., Schattenkerk, J., Miedema, F., & Tersmette, M. (1992). Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell tropic virus population. J. Virol., 66, 1354–1360.
Shields, P., & Adams, D. (2002). Chemokines and chemokine receptor interactions and functions in chemokine receptors and AIDS. New York: Dekker.
Simon, V., Zennou, V., Murray, D., Huang, Y., Ho, D., & Bieniasz, P. (2005). Natural variation in Vif: differential impact on APOBEC3G/3F and a potential role in HIV-1 diversification. PLoS Pathog., 1, e6.
Skrabal, K., Low, A., Dong, W., Sing, T., Cheung, P., Mammano, F., & Harrigan, R. (2007). Determining human immunodeficiency virus coreceptor use in a clinical setting: degree of correlation between two phenotypic assays and a bioinformatic model. J. Clin. Microbiol., 45, 279–284.
Smith, J. M. (1982). Evolution and the theory of games. Cambridge: Cambridge University Press.
Van Rij, R., Blaak, H., Visser, J., Brouwer, M., Rientsma, R., Broersen, S., de Roda Husman, A., & Shuitemaker, H. (2000). Differential coreceptor expression allows for independent evolution of non-syncytium-inducing and syncytium-inducing HIV1. J. Clin. Invest., 106, 1039–1052.
Van’t Wout, A., Blaak, H., Ran, L., Brouwer, M., Kuiken, C., & 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, 5099–5107.
Vignuzzi, M., Stone, J. K., Arnold, J. J., Cameron, C. E., & Andino, R. (2006). Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature, 439, 344–348.
Wiegel, F. W., & Perelson, A. S. (2004). Some scaling principles for the immune system. Immunol. Cell Biol., 82, 127–131.
Wodarz, D. (2001). Cytoxic T-lymphocyte memory, virus clearance and antigenic heterogeneity. Proc. R. Soc. Lond. B, 268, 429–436.
Wodarz, D. (2006). Killer cell dynamics: mathematical and computational approaches to immunology. Berlin: Springer.
Wodarz, D., & Krakauer, D. C. (2000). Defining CTL induced pathology: implications for HIV. Virology, 274, 94–104.
Wodarz, D., & Nowak, M. (1998). The effect of different immune responses on the evolution of virulent CXCR4 trophic HIV. Proc. R. Soc. Lond. B Biol. Sci., 265, 2149–2158.
Wodarz, D., Lloyd, A. L., Jansen, V. A. A., & Nowak, M. A. (1999). Dynamics of macrophage and T-cell infection by HIV. J. Theor. Biol., 196, 101–113.
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Bewick, S., Wu, J., Lenaghan, S.C. et al. The R5 to X4 Coreceptor Switch: A Dead-End Path, or a Strategic Maneuver?. Bull Math Biol 73, 2339–2356 (2011). https://doi.org/10.1007/s11538-010-9625-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11538-010-9625-1