Novel Delivery System Enhances Efficacy of Antiretroviral Therapy in Animal Model for HIV-1 Encephalitis

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.

Intact Lipid Rafts Regulate HIV-1 Tat Protein-Induced Activation of the Rho Signaling and Upregulation of P-Glycoprotein in Brain Endothelial Cells

“…In the context of HAART, it is important to note that P-gp limits brain entry of HIV-1 protease inhibitors. Thus, the ability of these drugs to achieve therapeutic concentrations in the brain is limited, thereby creating a potential sanctuary for viral replication Ronaldson et al, 2008;Spitzenberger et al, 2007). Both viral factors and drugs used for HAART may be responsible for upregulation of P-gp in HIV-1-infected patients on antiretroviral therapy.…”

Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: Current status of dopamine system vulnerability in NeuroAIDS

“…The brain pathology of SCID mice infected with HIV-monocytes has been demonstrated to be similar to that of humans infected with HIV, including prominent characteristics of encephalitis (e.g., multinucleated giant cells, astrogliosis, and neuronal toxicity) , cytokine and chemokine upregulation (Persidsky et al, , 1997, and even behavioral abnormalities (Avgeropoulos et al, 1998). To date, researchers continue to use the SCID model not only for characterization of HIV pathology, but for studying therapeutic interventions of HIV (Cook-Easterwood et al, 2007;Spitzenberger et al, 2007). Even before the use of the SCID mouse model, transgenic mice which express various HIV-proteins have been used to study HIV related syndromes (Klotman et al, 1995), and the effect of HIV-proteins on the CNS (Keswani et al, 2006;Toneatto et al, 1999) (see Persidsky et al, 2005 for review of rodent HIV models).…”

Development of HIV Reservoir Targeted Long Acting Nanoformulated Antiretroviral Therapies

“…It was found that Pluronic ® P85 could enhance drug tissue permeability of ritonavir [75]. Spitzenberger et al [76] demonstrated that P85 could facilitate antiretroviral drug efficacy in a severe combined immunodeficiency (SCID) mouse model of viral encephalitis. Interestingly, 0.2% P85 itself also exhibited antiretroviral effects (13.4% HIV-1p24 positive) compared with control group (68.5% HIV-1p24 positive) after 2 weeks treatment.…”