Human Immunodeficiency Virus Persistence Despite Prolonged Combination Therapy: Modeling and Control Strategies

该项目的主要目标是在高效抗逆转录病毒疗法(HAART)的背景下建立人类免疫缺陷病毒(HIV)持续时间和控制策略的数学模型。尽管HAART通常可以将HIV感染者的血浆病毒载量抑制到当前标准检测方法的检测下限以下，但它不能从患者身上根除病毒。HIV可以在静息记忆的CD4+T细胞(潜伏库)中被识别出来，并在HAART存在的情况下持续较低的水平，持续一段时间。这些潜伏感染的细胞腐烂缓慢，但当被相关抗原激活时，可以产生病毒粒子。病毒载量低、持续时间长、潜伏期极慢的潜伏宿主的致病机制还不完全清楚。该项目的第一部分是开发新的数学模型，以研究艾滋病毒治疗期间病毒和潜在宿主的长期动态。将对模型进行分析，并将预测与数据进行比较，以测试这些机制。由于目前HIV感染需要终生治疗，因此迫切需要有效的控制策略来降低治疗成本和与长期使用药物相关的毒性。该项目的第二部分是利用我们在第一部分中开发的艾滋病毒持久性模型来制定控制策略。使用所开发的模型还可以获得实际的治疗计划，例如结构化治疗中断。该项目代表了一项基于数学模型制定控制策略的努力，这些模型的预测与我们关于艾滋病毒感染和长期治疗的大部分知识相一致。结果加深了我们对HIV持续存在的生物学事件的理解，并可能对HAART时代的HIV感染管理具有重要意义。如果控制策略，特别是那些中断的治疗方案，能够提供与最大限度使用药物的持续治疗相似的治疗益处，它们将显著减轻经济负担，将药物毒性降至最低，并提高艾滋病毒患者的生活质量。此外，该项目还为数学系和生物系以及奥克兰大学新医学院的本科生和研究生提供了广泛的跨学科培训机会。这项研究将被纳入研究生数学生物学课程和各种本科生研究项目，其中大多数优先考虑少数民族学生。

The major goal of this project is to develop mathematical models of human immunodeficiency virus (HIV) persistence and control strategies in the setting of highly active antiretroviral therapy (HAART). Although HAART can often suppress the plasma viral loads of HIV-infected individuals to below the detection limit of current standard assays, it cannot eradicate the virus from patients. HIV can be identified in resting memory CD4+ T cells (the latent reservoir) and persists at a low level in the presence of HAART for a prolonged period of time. These latently infected cells decay slowly, but can produce virions when activated by their relevant antigens. The mechanisms underlying low viral load persistence and extremely slow decay of the latent reservoir are not fully understood. The first part of this project is to develop novel mathematical models to study the long-term dynamics of both virus and the latent reservoir during HIV treatment. Models will be analyzed and predictions will be compared with data to test the mechanisms. Since HIV infection requires lifelong therapy at present, efficient control strategies are urgently needed to reduce treatment cost and toxicity associated with long-term drug use. The second part of the project is to develop control strategies using the models of HIV persistence we developed in the first part. Practical treatment schedules such as structured treatment interruptions are also obtained using the developed models. The project represents an effort to develop control strategies based on mathematical models whose predictions agree with much of our knowledge about HIV infection and prolonged treatment. Results improve our understanding of the biological events underlying HIV persistence and may have important implications for the management of HIV infection in the era of HAART. If the control strategies, particularly those interrupted treatment schedules, can be shown to provide similar treatment benefits as the continuous therapy with maximum drug use, they will significantly reduce the financial burden, minimize drug toxicity, and improve the life quality of HIV patients. Additionally, the project provides extensive interdisciplinary training opportunities for undergraduate and graduate students from the math and biology departments, as well as the new medical school at Oakland University. The research will be incorporated into a graduate mathematical biology course and a variety of undergraduate research programs, most of which place priority on involving minority students.