Novel delivery system enhances efficacy of antiretroviral therapy in animal model for HIV-1 encephalitis.
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.
Spitzenberger
Timothy J
TJ
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Heilman
David
D
Diekmann
Casey
C
Batrakova
Elena V
EV
Kabanov
Alexander V
AV
Gendelman
Howard E
HE
Elmquist
William F
WF
Persidsky
Yuri
Y
D015526:AIDS Dementia Complex / Q000188:drug therapy*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D005079:Excipients; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use*; D054303:HIV Reverse Transcriptase / Q000096:biosynthesis; D015497:HIV-1; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use; D008264:Macrophages / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D019888:Nelfinavir / Q000008:administration & dosage* / Q000627:therapeutic use*; D011060:Poloxalene / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005079:Excipients; D017320:HIV Protease Inhibitors; C422648:pluronic block copolymer p85; D019259:Lamivudine; D015215:Zidovudine; D011060:Poloxalene; D054303:HIV Reverse Transcriptase; D019888:Nelfinavir