SUBMUCOSAL SIV PERSISTENCE DESPITE HAART

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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转运体)和CYP3A4(一种CYP-450同工酶)在小动物模型中的表达，在这些模型中，生物利用度和峰值血浆浓度被确定为HPIs抗HIV疗效的衡量标准。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，特别是在HIV阳性患者的胃粘膜下层。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CYP3A4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。 项目开始日期取决于IACUC申请的提交和批准。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 ABCtransporter) and Cyp3A4 (a CYP-450 isozyme) expression in small animal 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 in the 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 Cyp3A4 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 start date is pending on the submission to and approval of the IACUC application.