Therapeutic Interventions for HIV-1 CNS Sequestration.

HIV-1 CNS 隔离的治疗干预。

• 批准号: 6870222
• 负责人: NATALIE D EDDINGTON
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870222
• 关键词: AIDS /HIV neuropathy; AIDS therapy; P glycoprotein; SCID mouse; SDS polyacrylamide gel electrophoresis; antiAIDS agent; blood brain barrier; caudate nucleus; central nervous system; drug resistance; human immunodeficiency virus 1; immunocytochemistry; immunopharmacology; immunotherapy; putamen; saquinavir; tight junctions; tissue /cell culture; western blottings; zidovudine

DESCRIPTION (provided by applicant): HIV-1 enters the Central Nervous System (CNS) after the primary infection and contributes to the neurological deficits observed in patients. Moderate to high viral titers are found in the CNS due to the fact that the majority of anti-retroviral agents are unable to achieve sufficient levels in the brain. The Blood Brain Barrier (BBB) possesses tight junctions and various Multi-Drug Resistance (MDR) transporters such as P-glycoprotein (Pgp) and Multi-drug Resistance Associated Protein (MRP-2), which serve to significantly minimize brain anti-retroviral drug delivery to the brain. Thus, the hypothesis of this therapeutic intervention proposal is that anti-retroviral drug delivery to the brain can be enhanced in order to manageHIV-1 related neuroinvasion by reversibly opening tight junctions and by modulation of MDR (P-glycoprotein,MRP) mediated efflux at the BBB. In order to test this hypothesis, the following three specific aims (SA) will be pursued SA1 To examine the ability of Zonula Occludens Toxin (Zot) to enhance the BBB transport, brain uptake and activity of two "model" antiretroviral agents (AZT, zidovudine) using cell culture techniques and the SCID mice. Preliminary studies have shown that Zot is capable of reversibly opening tight junctions in the BBB, as well as significantly (p < 0 05) increasing brain levels of hydrophilic and hydrophobic agents (e g, paclitaxel, doxorubicin).Uninfected SCID mice and SCID mice inoculated with HIV-1 infected monocytes in the brain caudate and putamen will be used. Antiretroviral brain levels and viral titers will be determined. SA 2 To examine the effect of MDR modulation on the BBB transport, brain uptake and activity of AZT and saquinavir (substrates of MRP-1 and Pgp) two "model" anti-retroviral agents using cell culture techniques and the SCID mouse model. To examine the effect of MDR modulation on the in vitro BBB transport and brain distribution of on AZT and saquinavir (substrates of MRp-2 and Pgp)using cell culture techniques and the SCID mice SA3.To examine the concomitant effect of Zot and the MDR inhibitors on the BBB transport, brain uptake and activity of AZT and saquinavir using SCID mice. Obtaining therapeutic CNS levels of anti-retroviral agents is essential to minimizing HIV-1 in the CNS. As such, this proposal offers a viable approach to address this complication of HIV/AIDS.

描述（由申请人提供）：HIV-1在主要感染后进入中枢神经系统（CNS），并导致患者观察到的神经缺陷。在中枢神经系统中发现了中等至高病毒滴度，因为大多数抗逆转录病毒药物无法在大脑中达到足够的水平。血脑屏障（BBB）具有紧密的连接点和各种多药耐药性（MDR）转运蛋白，例如P-糖蛋白（PGP）和多药耐药性相关蛋白（MRP-2），这些蛋白质（MRP-2）可显着最大程度地减少脑抗脑抗逆转录病毒药物的递送。因此，这一治疗性干预建议的假设是，可以通过可逆地打开紧密的连接和MDR（P-甘同蛋白，MRP）MEDIAIDEFFLUX在BBB处通过可逆性的紧密连接来管理抗逆转录病毒药物向大脑的递送，以便通过可逆地打开紧密的连接来管理与HIV-1相关的神经侵化。为了检验这一假设，将追求以下三个特定目标（SA），以检查卵巢封闭剂毒素（ZOT）的能力，以增强BBB运输，使用细胞培养技术和刻板型鼠标的BBB运输，脑吸收和活性。初步研究表明，ZOT能够在BBB中可逆地打开紧密连接，并显着（P <0 05）增加了脑疏水性和疏水剂的大脑水平（E G，EG，Paclitaxel，adcorubibicin，Unininininininininin fementecid小鼠。将确定抗逆转录病毒脑水平和病毒滴度。 SA 2检查了MDR调制对AZT和Saquinavir（MRP-1和PGP的底物）的BBB转运，脑部吸收以及使用细胞培养技术和SCID小鼠模型的两个“模型”抗逆转录病毒剂的影响。检查MDR调节对使用细胞培养技术以及SCID小鼠SA3的AZT和Saquinavir（MRP-2和PGP的底物）的体外BBB传输和大脑分布的影响，以检查ZOT和MDR抑制剂对BBB运输，脑摄取和AZT和Saquir的影响。获得抗逆转录病毒药物的治疗性中枢神经系统水平对于最大程度地减少中枢神经系统中的HIV-1是必不可少的。因此，该提案提供了一种可行的方法来解决这种艾滋病毒/艾滋病的复杂性。