Differential equation analyses of latent HIV reservoirs

潜在 HIV 储存库的微分方程分析

• 批准号: 6746110
• 负责人: John E. Mittler
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746110
• 关键词: AIDS therapy; HIV infections; antiviral agents; biochemical evolution; cell population study; combination chemotherapy; computer assisted sequence analysis; dendritic cells; disease reservoirs; helper T lymphocyte; human data; latent virus infection; macrophage; mathematical model; model design /development; statistics /biometry; virus genetics; virus infection mechanism

DESCRIPTION (provided by applicant): Although combination antiretroviral drug therapies rapidly push plasma HIV-1 RNA concentrations below limits of detection, latently infected resting memory CD4+ T-cells can persist for years despite fully suppressive therapy. The intrinsic half-life of these cells has been estimated to be six months or longer. Recent studies suggest that populations of latently infected cell populations may persist for 60 years or more despite highly suppressive combination antiretroviral therapy. These long-lived infected cells, therefore, are thought to be the major impediment to curing patients of HIV-1 with antiretroviral drugs. However, they may not be the only reservoir for infectious virus: virus may also persist for long periods of time on follicular dendritic cells and in tissue macrophages. Current procedures for estimating infected cell half-lives are limited to tissues, such as PBMC, which can be sampled quantitatively over time. In this study I propose to use data on the decrease in genetic divergence (i.e., distance from the founder virus in patient) that occurs following antiretroviral therapy to draw inferences concerning the turnover of latently infected cell reservoirs. Declines in genetic divergence will be obtained using maximum likelihood trees. To quantify these declines I will develop mathematical models for viral dynamics that account for viral mutation and the decay of different infected cell compartments following antiretroviral therapy. Parameters for the diversification of virus in short-lived infected cells will be obtained from pre-treatment divergence data, while the input of virus into the latent reservoir will be modeled using viral load data. These models will be tested from published data and data obtained from experimental collaborators on HIV-1 sequences from infected children and adults who have gone on antiretroviral therapy. The estimates obtained from these models will be compared to estimates obtained from the decay in the density of latently infected cells following antiretroviral therapy. These models may give new insights into why therapies do not eradicate virus from the body and may give clinicians new ideas for strategies for targeting viruses in long-lived cellular compartments.

描述（由申请人提供）：尽管抗逆转录病毒药物疗法的组合迅速将血浆HIV-1 RNA浓度推向检测限制，但尽管完全抑制了疗法，但受到潜在感染的静止记忆CD4+ T细胞仍可以持续多年。这些细胞的内在半衰期估计为六个月或更长时间。最近的研究表明，尽管高度抑制性抗逆转录病毒疗法，但受到潜在感染的细胞种群的种群可能会持续60年或更长时间。因此，这些长寿命感染的细胞被认为是治愈HIV-1患者使用抗逆转录病毒药物的主要障碍。但是，它们可能不是传染病病毒的唯一水库：病毒在卵泡树突状细胞和组织巨噬细胞中也可能长时间持续存在。当前估计感染细胞半衰期的程序仅限于组织，例如PBMC，可以随时间进行定量采样。在这项研究中，我建议使用有关在抗逆转录病毒治疗后发生的遗传差异降低（即与患者创始人病毒的距离）的数据，以提出有关潜在受感染细胞储层的转换的推论。遗传差异的下降将使用最大似然树获得。为了量化这些下降，我将开发用于病毒动力学的数学模型，这些模型解释了病毒突变和抗逆转录病毒治疗后不同感染细胞室的衰减。病毒在短暂感染细胞中多元化的参数将从预处理差异数据中获得，而病毒对潜在储层的输入将使用病毒载荷数据进行建模。这些模型将从已发表的数据和从接受抗逆转录病毒疗法的受感染儿童和成人的HIV-1序列获得的实验合作者获得的数据中进行测试。从这些模型中获得的估计值将与从抗逆转录病毒治疗后潜在感染细胞的密度中获得的估计值进行比较。这些模型可能会给人们新的见解，说明为什么疗法不会从体内消除病毒，并可能为临床医生提供新的想法，以实现长寿细胞隔室中靶向病毒的策略。