Skip to main content

Advertisement

SpringerLink
Log in

Latently Infected Cell Activation: A Way to Reduce the Size of the HIV Reservoir?

  • Original Article
  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

While antiretroviral drugs can drive HIV to undetectably low levels in the blood, eradication is hindered by the persistence of long-lived, latently infected memory CD4 T cells. Immune activation therapy aims to eliminate this latent reservoir by reactivating these memory cells, exposing them to removal by the immune system and the cytotoxic effects of active infection. In this paper, we develop a mathematical model that investigates the use of immune activation strategies while limiting virus and latent class rebound. Our model considers infection of two memory classes, central and transitional CD4 T cells and the role that general immune activation therapy has on their elimination. Further, we incorporate ways to control viral rebound by blocking activated cell proliferation through anti proliferation therapy. Using the model, we provide insight into the control of latent infection and subsequently into the long term control of HIV infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Archin, N. M., & Margolis, D. M. (2006). Attacking latent HIV provirus: from mechanism to therapeutic strategies. Curr. Opin. HIV & AIDS, 1, 134–140.

    Google Scholar 

  • Archin, N. M., Eron, J. J., Palmer, S., Hartmann-Duff, A., Martinson, J. A., Wiegand, A., Bandarenko, N., Schmitz, J. L., Bosch, R. J., Landay, A. L., Coffin, J. M., & Margolis, D. M. (2008). Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells. AIDS, 22, 1131–1135.

    Article  Google Scholar 

  • Blankson, J. N., Persaud, D., & Siliciano, R. F. (2002). The challenge of viral reservoirs in HIV-1 infection. Annu. Rev. Med., 53(1), 557–593.

    Article  Google Scholar 

  • Blas-Garcia, A., Esplugues, J. V., & Apostolova, N. (2011). Twenty years of HIV-1 non-nucleoside reverse transcriptase inhibitors: time to reevaluate their toxicity. Curr. Med. Chem., 18(14), 2186–2195.

    Google Scholar 

  • Burnett, J. C., Lim, K., Calafi, A., Rossi, J. J., Schaffer, D. V., & Arkin, A. P. (2010). Combinatorial latency reactivation for HIV-1 subtypes and variants. J. Virol., 84(12), 5958–5974.

    Article  Google Scholar 

  • Callaway, D. S., & Perelson, A. S. (2002). HIV-1 infection and low steady state viral loads. Bull. Math. Biol., 64(1), 29–64.

    Article  Google Scholar 

  • Chomont, N., El-Far, M., Ancuta, P., Trautmann, L., Procopio, F. A., Yassine-Diab, B., Boucher, G., Boulassel, M.-R., Ghattas, G., Brenchley, J. M., Schacker, T. W., Hill, B. J., Douek, D. C., Routy, J.-P., Haddad, E. K., & Sékaly, R.-P. (2009). HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat. Med., 15, 893–900.

    Article  Google Scholar 

  • Chomont, N., DaFonseca, S., Vandergeeten, C., Ancuta, P., & Sékaly, R.-P. (2011). Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV. Curr. Opin. HIV & AIDS, 6, 30–36.

    Article  Google Scholar 

  • Chun, T. W., Carruth, L., Finzi, D., Shen, X., DiGiuseppe, J. A., Taylor, H., Hermankova, M., Chadwick, K., Margolick, J., Quinn, T. C., Kuo, Y. H., Brookmeyer, R., Zeiger, M. A., Barditch-Crovo, P., & Siliciano, R. F. (1997a). Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature, 387, 183–188.

    Article  Google Scholar 

  • Chun, T. W., Stuyver, L., Mizell, S. B., Ehler, L. A., Mican, J. A. M., Baseler, M., Lloyd, A. L., Nowak, M. A., & Fauci, A. S. (1997b). Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl. Acad. Sci. USA, 94(24), 13193–13197.

    Article  Google Scholar 

  • Chun, T. W., Engel, D., Berrey, M. M., Shea, T., Corey, L., & Fauci, A. S. (1998). Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. Proc. Natl. Acad. Sci. USA, 95(15), 8869–8873.

    Article  Google Scholar 

  • Chun, T. W., Engel, D., Mizell, S. B., Hallahan, C. W., Fischette, M., Park, S., Davey, R. T. Jr., Dybul, M., Kovacs, J. A., Metcalf, J. A., Mican, J. M., Berrey, M. M., Corey, L., Lane, H. C., & Fauci, A. S. (1999). Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat. Med., 5(6), 651–655.

    Article  Google Scholar 

  • Chun, T. W., Justement, J. S., Moir, S., Hallahan, C. W., Maenza, J., Mullins, J. I., Collier, A. C., Corey, L., & Fauci, A. S. (2007). Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J. Infect. Dis., 195, 1762–1764.

    Article  Google Scholar 

  • Contreras, X., Schweneker, M., Chen, C.-S., McCune, J. M., Deeks, S. G., Martin, J., & Peterlin, B. M. (2009). Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J. Biol. Chem., 284, 6782–6789.

    Article  Google Scholar 

  • d’Arminio Monforte, A., Lepri, A., & Rezza, G. (2000). Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. AIDS, 14, 499–507.

    Article  Google Scholar 

  • Davey, R. T., Chaitt, D. G., Piscitelli, S. C., Wells, M., Kovacs, J. A., Walker, R. E., Falloon, J., Polis, M. A., Metcalf, J. A., Masur, H., Fyfe, G., & Lane, H. C. (1997). Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. J. Infect. Dis., 175(4), 781–789.

    Article  Google Scholar 

  • Di Mascio, M., Dornadula, G., Zhang, H., Sullivan, J., Xu, Y., Kulkosky, J., Pomerantz, R. J., & Perelson, A. S. (2003). In a subset of subjects on highly active antiretroviral therapy, human immunodeficiency virus type 1 RNA in plasma decays from 50 to <5 copies per milliliter, with a half-life of 6 months. J. Virol., 77, 2271–2275.

    Article  Google Scholar 

  • Di Mascio, M., Percus, J. K., Percus, O. E., Markowitz, M., Ho, D. D., & Perelson, A. S. (2005). Duration of an intermittent episode of viremia. Bull. Math. Biol., 67, 885–900.

    Article  MathSciNet  Google Scholar 

  • Dornadula, G., Zhang, H., VanUitert, B., Stern, J., Livornese, L., Ingerman, M. J., Witek, J., Kedanis, R. J., Natkin, J., DeSimone, J., & Pomerantz, R. J. (1999). Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA J. Am. Med. Assoc., 282(17), 1627–1632.

    Article  Google Scholar 

  • Finzi, D., Hermankova, M., Pierson, T., Carruth, L. M., Buck, C., Chaisson, R. E., Quinn, T. C., Chadwick, K., Margolick, J., Brookmeyer, R., Gallant, J., Markowitz, M., Ho, D. D., Richman, D. D., & Siliciano, R. F. (1997). Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science, 278(5341), 1295–1300.

    Article  Google Scholar 

  • Finzi, D., Blankson, J., Siliciano, J. D., Margolick, J. B., Chadwick, K., Pierson, T., Smith, K., Lisziewicz, J., Lori, F., Flexner, C., Quinn, T. C., Chaisson, R. E., Rosenberg, E., Walker, B., Gange, S., Gallant, J., & Siliciano, R. F. (1999). Latent infection of CD4+ T cells provides a mechanism for life long persistence of HIV-1, even in patients on effective combination therapy. Nat. Med., 5, 512–517.

    Article  Google Scholar 

  • Fraser, C., Ferguson, N. M., Ghani, A. C., Prinsa, J. M., Langea, J. M. A., Goudsmitb, J., Anderson, R. M., & de Wolf, F. (2000). Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. AIDS, 14, 659–669.

    Article  Google Scholar 

  • Freed, E. O., & Martin, M. A. (2007). HIVs and their replication. In D. M. Knipe & P. M. Howley (eds.), Field’s Virology, pp. 2107–2186. Wolters Kluwer Health/Lippincott Williams & Wilkins, Philadelphia

    Google Scholar 

  • Geeraert, L., Kraus, G., & Pomerantz, R. J. (2008). Hide-and-seek: The challenge of viral persistence in HIV-1 infection. Annu. Rev. Med., 59(1), 487–501.

    Article  Google Scholar 

  • Gunthard, H. F., Havlir, D. V., Fiscus, S., Zhang, Z.-Q., Eron, J., Mellors, J., Gulick, R., Frost, S. D. W., Brown, A. J. L., Schleif, W., Valentine, F., Jonas, L., Meibohm, A., Ignacio, C. C., Isaacs, R., Gamagami, R., Emini, E., Haase, A., Richman, D. D., & Wong, J. K. (2001). Residual human immunodeficiency virus (HIV) type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years. J. Infect. Dis., 183(9), 1318–1327.

    Article  Google Scholar 

  • Harrigan, P. R., Whaley, M., & Montaner, J. S. (1999). Rate of HIV-1 RNA rebound upon stopping antiretroviral therapy. AIDS, 13, F59–F62.

    Article  Google Scholar 

  • Ho, D. 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.

    Article  Google Scholar 

  • Hockett, R. D., Kilby, J. M., Derdeyn, C. A., Saag, M. S., Sillers, M., Squires, K., Chiz, S., Nowak, M. A., Shaw, G. M., & Bucy, R. P. (1999). Constant mean viral copy number per infected cell in tissues regardless of high, low, or undetectable plasma HIV RNA. J. Exp. Med., 17, 1545–1554.

    Article  Google Scholar 

  • Hunt, P. W., Brenchley, J., Sinclair, E., McCune, J. M., Roland, M., Shafer, K. P., Hsue, P., Emu, B., Krone, M., Lampiris, H., Douek, D., Martin, J. N., & Deeks, S. G. (2008). Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J. Infect. Dis., 197(1), 126–133.

    Article  Google Scholar 

  • Jones, L. E., & Perelson, A. S. (2007). Transient viremia, plasma viral load, and reservoir replenishment in HIV-infected patients on antiretroviral therapy. J. Acquir. Immune Defic. Syndr., 45, 483–493.

    Article  Google Scholar 

  • Kaufmann, G. R., Bloch, M., Zaunders, J. J., Smith, D., & Cooper, D. A. (2000). Long-term immunological response in HIV-1-infected subjects receiving potent antiretroviral therapy. AIDS, 14(8), 959–969.

    Article  Google Scholar 

  • Kim, H., & Perelson, A. S. (2006). Viral and latent reservoir persistence in HIV-1 infected patients on therapy. PLoS Comput. Biol., 2, e135.

    Article  Google Scholar 

  • Kovochich, M., Marsden, M. D., & Zack, J. A. (2011). Activation of latent HIV using drug-loaded nanoparticles. PLoS ONE, 6, e18270.

    Article  Google Scholar 

  • Lehrman, G., Hogue, I. B., Palmer, S., Jennings, C., Spina, C. A., Wiegand, A., Landay, A. L., Coombs, R. W., Richman, D. D., Mellors, J. W., Coffin, J. M., Bosch, R. J., & Margolis, D. M. (2005). Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. The Lancet, 366(9485), 549–555.

    Article  Google Scholar 

  • Lok, J. J., Bosch, R. J., Benson, C. A., Collier, A. C., Robbins, G. K., Shafer, R. W., Hughes, M. D., & ALLRT team (2010). Long-term increase in CD4+ T-cell counts during combination antiretroviral therapy for HIV-1 infection. AIDS, 24(12), 1867–1876.

    Article  Google Scholar 

  • Margolis, D. M. (2010). Mechanisms of HIV latency: an emerging picture of complexity. Curr. HIV/AIDS Rep., 7, 37–43.

    Article  Google Scholar 

  • Markowitz, M., Louie, M., Hurley, A., Sun, E., Di Mascio, M., Perelson, A. S., & Ho, D. D. (2003). A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and T-cell decay in vivo. J. Virol., 77, 5037–5038.

    Article  Google Scholar 

  • Mellberg, T., Gonzalez, V., Lindkvist, A., Eden, A., Sonnerborg, A., Sandberg, J., Svennerholm, B., & Gisslen, M. (2011). Rebound of residual plasma viremia after initial decrease following addition of intravenous immunoglobulin to effective antiretroviral treatment of HIV. AIDS Res. Ther., 8(1), 21.

    Article  Google Scholar 

  • Nettles, R. E., Kieffer, T. L., Kwon, P., Monie, D., Han, Y., Parsons, T., Cofrancesco, J. Jr., Gallant, J. E., Quinn, T. C., Jackson, B., Flexner, C., Carson, K., Ray, S., Persaud, D., & Siliciano, R. F. (2005). Intermittent HIV-1 viremia (blips) and drug resistance in patients receiving HAART. JAMA J. Am. Med. Assoc., 293(7), 817–829.

    Article  Google Scholar 

  • Palmer, S., Maldarelli, F., Wiegand, A., Bernstein, B., Hanna, G. J., Brun, S. C., Kempf, D. J., Mellors, J. W., Coffin, J. M., & King, M. S. (2008). Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc. Natl. Acad. Sci. USA, 105(10), 3879–3884.

    Article  Google Scholar 

  • Perelson, A. S., Essunger, P., Cao, Y., Vesanen, M., Hurley, A., Saksela, K., Markowitz, M., & Ho, D. D. (1997). Decay characteristics of HIV-1-infected compartments during combination therapy. Nature, 387, 188–191.

    Article  Google Scholar 

  • Ramratnam, B., Bonhoeffer, S., Binley, J., Hurley, A., Zhang, L., Mittler, J. E., Markowitz, M., Moore, J. P., Perelson, A. S., & Ho, D. D. (1999). Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet, 354, 1782–1785.

    Article  Google Scholar 

  • Rong, L., & Perelson, A. S. (2009a). Modeling HIV persistence, the latent reservoir, and viral blips. J. Theor. Biol., 260(2), 308–331.

    Article  Google Scholar 

  • Rong, L., & Perelson, A. S. (2009b). Asymmetric division of activated latently infected cells may explain the decay kinetics of the HIV-1 latent reservoir and intermittent viral blips. Math. Biosci., 217(1), 77–87. Mathematical Models of Inflammation.

    Article  MathSciNet  MATH  Google Scholar 

  • Rong, L., & Perelson, A. S. (2009c). Modeling latently infected cell activation: Viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy. PLoS Comput. Biol., 5, e1000533.

    Article  MathSciNet  Google Scholar 

  • Sachsenberg, N., Perelson, A. S., Yerly, S., Schockmel, G. A., Leduc, D., Hirschel, B., & Perrin, L. (1998). Turnover of CD4 and CD8 T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. J. Exp. Med., 187, 1295–1303.

    Article  Google Scholar 

  • Sallusto, F., Geginat, J., & Lanzavecchia, A. (2004). Central memory and effector memory T cell subsets: Function, generation, and maintenance. Annu. Rev. Immunol., 22, 745–763.

    Article  Google Scholar 

  • Sedaghat, A. R., Siciliano, R. F., & Wilke, C. O. (2008). Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAART. BMC Infect. Dis., 8, 1–14.

    Article  Google Scholar 

  • Shen, L., & Siliciano, R. F. (2008). Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection. J. Allergy Clin. Immunol., 122, 22–28.

    Article  Google Scholar 

  • Siliciano, J. D., Kajdas, J., Finzi, D., Quinn, T. C., Chadwick, K., Margolick, J. B., Kovacs, C., Gange, S. J., & Siliciano, R. F. (2003). Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat. Med., 9, 727–728.

    Article  Google Scholar 

  • Siliciano, J. D., Lai, J., Callender, M., Pitt, E., Zhang, H., Margolick, J. B., Gallant, J. E., Cofrancesco, J. Jr., Moore, R. D., Gange, S. J., & Siliciano, R. F. (2007). Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J. Infect. Dis., 195, 833–836.

    Article  Google Scholar 

  • Simon, V., & Ho, D. D. (2003). HIV-1 dynamics in vivo: implications for therapy. Nat. Rev., Microbiol., 1, 181–190.

    Article  Google Scholar 

  • Smith, R., & Aggarwala, B. (2009). Can the viral reservoir of latently infected CD4 T cells be eradicated with antiretroviral HIV drugs? J. Math. Biol., 59, 697–715.

    Article  MathSciNet  MATH  Google Scholar 

  • Stafford, M. A., Corey, L., Cao, Y., Daar, E. S., Ho, D. D., & Perelson, A. S. (2000). Modeling plasma virus concentration during primary HIV infection. J. Theor. Biol., 203, 285.

    Article  Google Scholar 

  • Suntharalingam, G., Perry, M. R., Ward, S., Brett, S. J., Castillo-Cortes, A., Brunner, M. D., & Panoskaltsis, N. (2006). Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med., 355, 1018–1028.

    Article  Google Scholar 

  • Wei, X., Ghosh, S. K., Taylor, M. E., Johnson, V. A., Emini, E. A., Deutsch, P., Lifson, J. D., Bonhoeffer, S., Nowak, M. A., Hahn, B. H., Saag, M. S., & Shaw, G. M. (1995). Viral dynamics in human immunodeficiency virus type 1 infection. Nature, 373, 117–122.

    Article  Google Scholar 

  • Wolschendorf, F., Duverger, A., Jones, J., Wagner, F. H., Huff, J., Benjamin, W. H., Saag, M. S., Niederweis, M., & Kutsch, O. (2010). Hit-and-run stimulation: a novel concept to reactivate latent HIV-1 infection without cytokine gene induction. J. Virol., 84(17), 8712–8720.

    Article  Google Scholar 

  • Yang, H. C., Shen, L., Siciliano, R. F., & Pomerantz, J. L. (2009). Isolation of a cellular factor that can reactivate latent HIV-1 without T cell activation. Proceedings of the National Academy of Science (USA) (pp. 6321–6325).

  • Yates, A., Stark, J., Klein, N., Antia, R., & Callard, R. (2007). Understanding the slow depletion of memory CD4+ T cells in HIV infection. PLoS Med., 4, e177.

    Article  Google Scholar 

  • Zhang, L., Ramratnam, B., Tenner-Racz, K., He, Y., Vesanen, M., Lewin, S., Talal, A., Racz, P., Perelson, A. S., Korber, B. T., Markowitz, M., & Ho, D. D. (1999). Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N. Engl. J. Med., 340, 1605–1613.

    Article  Google Scholar 

Download references

Acknowledgement

SMC acknowledges support from NSF grant DMS-1022865. We thank the reviewers for their valuable comments and suggestions.

Author information

Authors and Affiliations

  1. Department of Mathematics and Computer Science, Hobart and Williams Smith Colleges, 300 Pulteney St., Geneva, NY, 14456, USA

    Jonathan Forde

  2. Durham, NC, USA

    Joseph M. Volpe

  3. Department of Mathematics, Virginia Tech, 416 McBryde Hall, Blacksburg, VA, 24060, USA

    Stanca M. Ciupe

Authors
  1. Jonathan Forde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph M. Volpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stanca M. Ciupe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan Forde.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Forde, J., Volpe, J.M. & Ciupe, S.M. Latently Infected Cell Activation: A Way to Reduce the Size of the HIV Reservoir?. Bull Math Biol 74, 1651–1672 (2012). https://doi.org/10.1007/s11538-012-9729-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11538-012-9729-x

Keywords

Search

Navigation