Novel delivery system enhances efficacy of antiretroviral therapy in animal model for HIV-1 encephalitis

Timothy J. Spitzenberger, David Heilman, Casey Diekmann, Elena V. Batrakova, Alexander V. Kabanov, Howard E. Gendelman, William F. Elmquist, Yuri Persidsky

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55 Scopus citations

Abstract

Most potent antiretroviral drugs (e.g., HIV-1 protease inhibitors) poorly penetrate the blood-brain barrier. Brain distribution can be limited by the efflux transporter, P-glycoprotein (P-gp). The ability of a novel drug delivery system (block co-polymer P85) that inhibits P-gp, to increase the efficacy of antiretroviral drugs in brain was examined using a severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE). Severe combined immunodeficiency mice inoculated with HIV-1 infected human monocyte-derived macrophages (MDM) into the basal ganglia were treated with P85, antiretroviral therapy (ART) (zidovudine, lamivudine and nelfinavir (NEL)), or P85 and ART. Mice were killed on days 7 and 14, and brains were evaluated for levels of viral infection. Antiviral effects of NEL, P85, or their combination were evaluated in vitro using HIV-1 infected MDM and showed antiretroviral effects of P85 alone. In SCID mice injected with virus-infected MDM, the combination of ART-P85 and ART alone showed a significant decrease of HIV-1 p24 expressing MDM (25% and 33% of controls, respectively) at day 7 while P85 alone group was not different from control. At day 14, all treatment groups showed a significant decrease in percentage of HIV-1 infected MDM as compared with control. P85 alone and combined ART-P85 groups showed the most significant reduction in percentage of HIV-1 p24 expressing MDM (8% to 22% of control) that were superior to the ART alone group (38% of control). Our findings indicate major antiretroviral effects of P85 and enhanced in vivo efficacy of antiretroviral drugs when combined with P85 in a SCID mouse model of HIVE.

Original languageEnglish (US)
Pages (from-to)1033-1042
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue number5
DOIs
StatePublished - May 16 2007

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Keywords

  • Blood-brain barrier (BBB)
  • CNS sanctuary
  • Drug delivery
  • HIV-1 encephalitis
  • P-glycoprotein
  • Pluronic P85

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Spitzenberger, T. J., Heilman, D., Diekmann, C., Batrakova, E. V., Kabanov, A. V., Gendelman, H. E., Elmquist, W. F., & Persidsky, Y. (2007). Novel delivery system enhances efficacy of antiretroviral therapy in animal model for HIV-1 encephalitis. Journal of Cerebral Blood Flow and Metabolism, 27(5), 1033-1042. https://doi.org/10.1038/sj.jcbfm.9600414