Abstract
Recently, an enzyme (Cre recombinase) has been developed by directed evolution that successfully removes the HIV genome from the nuclear DNA of infected cells. To explore this idea further, we hypothesized that a replication deficient virus (called “police virus”), added externally, can deliver such a recombinase which excises the integrated HIV DNA from the genome of infected cells. Such a “police virus” could attack and remove the integrated provirus which is not possible using contemporary strategies. The hypothesis was tested by developing a mathematical model that describes the dynamics of virus-host cell interaction and the consequences of introducing the “police virus”. The simulations show that such a therapeutic vector may eradicate all HIV viruses from the system in the long term. All components of the HIV infection (free virus, latently, and actively infected cells) can be cleared and the system ends up only with susceptible CD4+ cells. The proposed model may provide new insights in the dynamical behavior and future alternative treatments of HIV.
Similar content being viewed by others
References
Bailey J, Blankson JN, Wind-Rotolo M, Siliciano RF (2004) Mechanisms of HIV-1 escape from immune responses and antiretroviral drugs. Curr Opin Immunol 16:470–476
Berencsi G, Minárovits J, Nász I, Földes I (1989) Prospects for the control of AIDS patients by introducing defective-HIV harbouring leukocytes. Med Hypotheses 30:223–228
Capodici J, Karikó K, Weissman D (2002) Inhibition of HIV-1 infection by small interfering RNA-mediated RNA interference. J Immunol 169:5196–5201
Chun TW, Fauci AS (1999) Latent reservoirs of HIV: obstacles to the eradication of virus. Proc Natl Acad Sci USA 96:10958–10961
Di Mascio M, Ribeiro RM, Markowitz M, Ho DD, Perelson AS (2004) Modeling the long-term control of viremia in HIV-1 infected patients treated with antiretroviral therapy. Math Biosci 188:47–62
Dropulić B, Hĕrmánková M, Pitha PM (1996) A conditionally replicating HIV-1 vector interferes with wild-type HIV-1 replication and spread. Proc Natl Acad Sci USA 93:11103–11108
Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, Quinn TC, Chaisson RE, Rosenberg E, Walker B, Gange S, Gallant J, Siliciano RF (1999) Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 5:512–517
Han Y, Wind-Rotolo M, Yang HC, Siliciano JD, Siliciano RF (2007) Experimental approaches to the study of HIV-1 latency. Nat Rev Microbiol 5:95–106
Johnson RP (2002) Mechanisms of protection against simian immunodeficiency virus infection. Vaccine 20:1985–1987
Johnson RP (2006) HIV pathogenesis and vaccine development. Top HIV Med 14:8–15
Klipp E, Herwig R, Kowald A, Wierling C (2009) Systems biology. Wiley, New York
Landi A, Mazzoldi A, Andreoni C, Bianchi M, Cavallini A, Laurino M, Ricotti L, Iuliano R, Matteoli B, Ceccherini-Nelli L (2008) Modelling and control of HIV dynamics. Comput Methods Programs Biomed 89:162–168
Layden TJ, Layden JE, Ribeiro RM, Perelson AS (2003) Mathematical modeling of viral kinetics: a tool to understand and optimize therapy. Clin Liver Dis 7:163–178
Marsden MD, Zack JA (2009) Eradication of HIV: current challenges and new directions. J Antimicrob Chemother 63:7–10
Nelson GW, Perelson AS (1995) Modeling defective interfering virus therapy for AIDS: conditions for DIV survival. Math Biosci 125:127–153
Nowak MA, Bangham CR (1996) Population dynamics of immune responses to persistent viruses. Science 272:74–79
Perelson AS (2002) Modelling viral and immune system dynamics. Nat Rev Immunol 2:28–36
Phillips AN (1996) Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271:497–499
Pierson T, McArthur J, Siliciano RF (2000) Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol 18:665–708
Qin XF, An DS, Chen IS, Baltimore D (2003) Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5. Proc Natl Acad Sci USA 100:183–188
Revilla T, García-Ramos G (2003) Fighting a virus with a virus: a dynamic model for HIV-1 therapy. Math Biosci 185:191–203
Ribeiro RM, Mohri H, Ho DD, Perelson AS (2002) In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: why are CD4+ but not CD8+ T cells depleted? Proc Natl Acad Sci USA 99:15572–15577
Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ (2009) The challenge of finding a cure for HIV infection. Science 323:1304–1307
Rong L, Perelson AS (2009) Modeling HIV persistence, the latent reservoir, and viral blips. J Theor Biol 260:308–331
Rong L, Feng Z, Perelson AS (2007) Emergence of HIV-1 drug resistance during antiretroviral treatment. Bull Math Biol 69:2027–2060
Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, Robbins GK, D’Aquila RT, Goulder PJ, Walker BD (2000) Immune control of HIV-1 after early treatment of acute infection. Nature 407:523–526
Sarkar I, Hauber I, Hauber J, Buchholz F (2007) HIV-1 proviral DNA excision using an evolved recombinase. Science 316:1912–1925
Schnell MJ, Johnson JE, Buonocore L, Rose JK (1997) Construction of a novel virus that targets HIV-1-infected cells and controls HIV-1 infection. Cell 90:849–857
Siliciano JD, Siliciano RF (2000) Latency and viral persistence in HIV-1 infection. J Clin Investig 106:823–825
Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, Stryker R, Johnson P, Labriola DF, Farina D, Manion DJ, Ruiz NM (1999) Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 341:1865–1873
Steinmeyer SH, Wilke CO (2009) Lethal mutagenesis in a structured environment. J Theor Biol 261:67–73
Wodarz D, Nowak MA (2002) Mathematical models of HIV pathogenesis and treatment. Bioessays 24:1178–1187
Xia X (2003) Estimation of HIV/AIDS parameters. Automatica 39:1983–1988
Zurakowski R, Teel AR (2006) A model predictive control based scheduling method for HIV therapy. J Theor Biol 238:368–382
Author information
Authors and Affiliations
Corresponding author
Additional information
The authors contributed equally to this article.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Zintzaras, E., Kowald, A. A mathematical model of HIV dynamics in the presence of a rescuing virus with replication deficiency. Theory Biosci. 130, 127–134 (2011). https://doi.org/10.1007/s12064-011-0119-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12064-011-0119-y