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 Eliot Gendelman, William F. Elmquist, Yuri Persidsky

Research output: Contribution to journalArticle

55 Citations (Scopus)

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

Fingerprint

Encephalitis
HIV-1
Animal Models
Severe Combined Immunodeficiency
Macrophages
Nelfinavir
P-Glycoprotein
Group Psychotherapy
Therapeutics
Brain
Pharmaceutical Preparations
HIV Protease Inhibitors
Aptitude
Lamivudine
Zidovudine
Virus Diseases
Drug Delivery Systems
Basal Ganglia
Blood-Brain Barrier
Antiviral Agents

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

Novel delivery system enhances efficacy of antiretroviral therapy in animal model for HIV-1 encephalitis. / Spitzenberger, Timothy J.; Heilman, David; Diekmann, Casey; Batrakova, Elena V.; Kabanov, Alexander V.; Gendelman, Howard Eliot; Elmquist, William F.; Persidsky, Yuri.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 27, No. 5, 16.05.2007, p. 1033-1042.

Research output: Contribution to journalArticle

Spitzenberger, TJ, Heilman, D, Diekmann, C, Batrakova, EV, Kabanov, AV, Gendelman, HE, Elmquist, WF & 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, vol. 27, no. 5, pp. 1033-1042. https://doi.org/10.1038/sj.jcbfm.9600414
Spitzenberger, Timothy J. ; Heilman, David ; Diekmann, Casey ; Batrakova, Elena V. ; Kabanov, Alexander V. ; Gendelman, Howard Eliot ; Elmquist, William F. ; Persidsky, Yuri. / Novel delivery system enhances efficacy of antiretroviral therapy in animal model for HIV-1 encephalitis. In: Journal of Cerebral Blood Flow and Metabolism. 2007 ; Vol. 27, No. 5. pp. 1033-1042.
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