SUBMUCOSAL SIV PERSISTENCE DESPITE HAART

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 为了了解高效抗逆转录病毒治疗（HAART）方案的药代动力学，蛋白酶抑制剂（HPI）组合在人类艾滋病毒/艾滋病患者中的药代动力学，临床前研究先前分析了P-gp（ABC转运蛋白）和Cyp 3A 4（一种α-450同工酶）在小模型中的表达，例如小鼠、大鼠和兔，其中测定生物利用度和峰值血浆水平作为HPI抗HIV功效的量度。然而，最近的研究表明，ABC-转运蛋白和β-450同工酶的表达显着的物种特异性变化，这可能会深刻地改变正确确定的治疗剂量的HPI，特别是GI-粘膜下层的HIV阳性患者。我们计划开发一种体外模型，尽管抗逆转录病毒治疗，SIV的持久性在肠道水库，并确定新的策略对抑制宿主因素，导致这种无效。我们假设P-gp和Cyp-3A 4均抑制HPI穿过肠道屏障的转运，并且抑制它们的策略将消除SIV感染猴模型中粘膜下病毒储库的持久性。该项目目前正在进行中。所有动物均已分配，动物均为SIV活跃感染。目前正在收集和处理样本，以检测病毒载量以及P-gp和Cyp-450 mRNA和蛋白质水平的表达水平。这些动物将很快接受酮康唑治疗，以分析对肠道储库的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. To understand the pharmacokinetics of the highly active anti-retroviral therapy (HAART) regimen, combinations of protease inhibitors (HPIs) in humans with HIV-AIDS, preclinical studies had previously analyzed both P-gp (an ABC transporter) and Cyp3A4 (a CYP-450 isozyme) expression in small models, such as mice, rats and rabbits, where bioavailability and peak plasma levels were determined as a measure of anti-HIV efficacy of HPIs. However, recent studies demonstrated significant species-specific variations in the expression of both ABC-transporters and CYP-450 isozymes, which may profoundly alter the correct determination of therapeutic dosing of HPIs, especially GI-submucosa of HIV-positive patients. We plan to develop an ex vivo model of SIV persistence in intestinal reservoirs despite antiretroviral therapy, and identify novel strategies towards inhibition of the host factors which cause this inefficacy. We hypothesize that both P-gp and Cyp-3A4 suppress HPI transport across intestinal barriers and strategies towards their inhibition will abrogate the persistence of submucosal viral reservoirs in SIVinfected monkey models. The project is currently in process. All animals have been assigned and animals are actively infected with SIV. Samples are currently being collected and processed for viral load and expression levels of P-gp and Cyp-450 mRNA and protein levels. The animals will soon be treated with ketoconozole for the analysis of the effects on intestinal reservoirs.