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。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 为了了解高效抗逆转录病毒疗法(HAART)联合使用蛋白酶抑制剂(HPI)在人类感染艾滋病毒/艾滋病(HIV-AIDS)患者中的药代动力学，临床前研究先前分析了P-gp(ABC转运体)和CYP3A4(一种CYP-450同工酶)在小鼠、大鼠和兔等小模型中的表达，这些模型的生物利用度和峰值血浆浓度被确定为HPI抗HIV疗效的指标。然而，最近的研究表明，ABC转运蛋白和CYP-450同工酶的表达存在显著的物种特异性差异，这可能深刻地改变HPI治疗剂量的正确确定，特别是HIV阳性患者的GI黏膜下层。我们计划开发一种尽管接受抗逆转录病毒治疗但仍在肠道储存库中持续存在的SIV体外模型，并确定抑制导致这种无效的宿主因素的新策略。我们假设P-gp和Cyp-3A4都能抑制HPI跨越肠道屏障的转运，而抑制它们的策略将在SIV感染的猴子模型中消除粘膜下病毒库的持久性。该项目目前正在进行中。所有动物都已被分配，动物都被活跃地感染了SIV。目前正在收集和处理样本，以检测P-gp和Cyp-450的病毒载量和表达水平。这些动物将很快被用酮康唑治疗，以分析对肠道储存库的影响。

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.