HIV 2-LTR Dynamics and Cryptic Viremia

描述(由申请人提供)：我们开发了一个简单的模型，说明在一种明显具有抑制作用的抗病毒方案中加入整合酶抑制剂如雷替格雷后，2-LTRHIV DNA表观结构的形成。当来自最近的raltegravir强化实验的2-LTR浓度数据符合我们的模型时，结果强烈地表明-LTRepisome正在抗病毒药物不能抑制HIV复制的隔室中形成。该项目的主要研究目标是开发特定的可检验假说，以指导未来的临床验证实验来证实这些发现。在血液中检测不到病毒的患者中，了解艾滋病毒复制可能继续的机制对于治疗和/或治愈艾滋病毒感染的努力至关重要。如果 隐匿性病毒血症持续存在，艾滋病毒阳性患者最终会发展为抗药性病毒和 被迫改变治疗方案。这项研究中建立的数学模型可能为检测和量化隐匿性病毒血症提供一种微创的实验方法。这是能够研究和消除艾滋病毒药物中这种现象的关键的第一步。我们将使用贝叶斯统计针对新的数据集验证我们的模型，开发允许我们计划其他测量的模型扩展，并开发优化信息的采样计划，同时将实验的成本和侵入性降至最低。

DESCRIPTION (provided by applicant): We have developed a simple model of the formation of 2-LTR HIV DNA episomes following the addition of integrase inhibitor such as raltegravir to an apparently suppressive antiviral regimen. When 2-LTR concentration data from recent raltegravir intensification experiments is fit to our model, the results strongly suggest that the -LTR episomes are being formed in a compartment where the antiviral drugs are unable to contain HIV replication. The primary research objective of this project is to develop specific testable hypotheses to guide a future clinical validation experiment to confirm these findings. Understanding the mechanisms by which HIV replication may continue in patients with no virus detectable in their blood is critically important to efforts to treat and/or cure HIV infection. If cryptic viremia persists, the HIV-positive patient will eventually develop drug-resistant virus and be forced to switch treatment regimens. The mathematical models developed in the proposed research may provide a minimally invasive experimental method to detect and quantify cryptic viremia. This is a critical first step in being able to study and eliminate this phenomenon in HIV medicine. We will use Bayesian statistics to validate our model against a new dataset, develop model extensions that allow us to plan for other measurements, and develop sampling schedules that optimize the information while minimizing the cost and invasiveness of the experiment.