Defining the causes and consequences of viral rebound

定义病毒反弹的原因和后果

• 批准号: 10057933
• 负责人: Matthew David Marsden
• 金额: $ 35.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057933
• 关键词: Affect; Alcohol consumption; Animal Model; Area; BLT mice; Bar Codes; CD4 Positive T Lymphocytes; Cells; Characteristics; Clinical Research; Disease Progression; Engineering; Event; Frequencies; Genetic Variation; Goals; HIV; Human; Hypersensitivity; Immune response; Immunity; Individual; Infection; Interruption; Kinetics; Length; Modeling; Monitor; Mus; Pathogenesis; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Plasma; Primary Infection; Process; Rest; Seeds; Source; Stimulus; Stress; Structure; Study models; T-Cell Activation; Testing; Time; Tissues; Vaccines; Variant; Viral Load result; Virus; antiretroviral therapy; clinically relevant; deep sequencing; humanized mouse; immune activation; immune reconstitution; immunoregulation; in vivo; insight; latent HIV reservoir; mouse model; viral rebound

Treatment of HIV-infected individuals with antiretroviral therapy (ART) can often suppress plasma viral loads to undetectable levels. However HIV persists during therapy and if ART is stopped then viral loads rapidly rebound allowing disease progression to continue. While it is clear that reservoirs of latently-infected CD4+ T cells and potentially other rare infected cells can serve as a source of replication-competent virus to rekindle infection, many questions remain about how and why rebound occurs if ART is discontinued. Particular areas where more study is needed include determining what can initiate the rebound process, how the timing and magnitude of rebound relates to the size and characteristics of the underlying latent reservoir, and defining what the consequences of allowing rebound to occur are. The overall goal of this PO1 application is to develop a more complete understanding of HIV rebound by using the bone marrow-liver-thymus (BLT) mouse, a highly relevant humanized mouse model for studying HIV in vivo. This model supports multi-lineage human immune reconstitution in many tissues within the mouse and represents one of the most advanced small animal models available for investigating HIV persistence and pathogenesis. We and others have shown that the BLT mouse model can be efficiently infected with HIV and forms authentic post-integration latency in resting CD4+ T cells. Viral loads can be suppressed using clinically relevant ART drugs, and if ART is stopped then viral loads quickly rebound. We have further advanced this model by utilizing a phenotypically neutral, genetically diverse barcoded HIV swarm to perform the infections. This allows a latent reservoir to be formed with diverse genetically tagged viruses. Rebound can then be tracked both through monitoring of viral loads to test the timing and magnitude of virus re-emergence in the plasma or tissues, and deep-sequencing of the rebounding virus to quantify the number of individual barcoded variants contributing to the rebound. This combined approach will provide an unprecedented view of HIV reservoir formation and viral rebound. In project 1 we will use this model to determine the contribution of Pre- ART infection time to spontaneous viral rebound (Aim 1), test whether common physiologic/pharmacologic stimuli alter the frequency of rebound (Aim 2), and quantify the effects of structured treatment interruption (STI) on the size and diversity of the latent HIV reservoir (Aim 3). Together, these studies will test key, clinically relevant parameters to determine how they affect rebound of HIV upon stopping ART, and will assess the consequences of allowing rebound to occur. This will provide new insights into the mechanisms contributing to HIV rebound.

用抗逆转录病毒疗法（ART）治疗HIV感染者通常可以抑制血浆病毒载量， 无法检测的水平。然而，HIV在治疗期间持续存在，如果停止ART，则病毒载量迅速增加。 反弹，使疾病继续发展。虽然很明显，潜在感染的CD 4 + T细胞的储存库， 细胞和其他可能罕见的感染细胞可以作为复制能力病毒的来源， 感染，许多问题仍然是如何和为什么反弹发生，如果停止抗逆转录病毒治疗。特定领域 需要进行更多的研究，包括确定什么可以启动反弹过程，时间和 回弹幅度与下伏潜在储层的大小和特征有关， 允许反弹发生的后果是什么。 本PO 1应用程序的总体目标是更全面地了解HIV反弹 通过使用骨髓-肝-胸腺（BLT）小鼠，用于研究的高度相关的人源化小鼠模型， 体内HIV。该模型支持小鼠体内许多组织中的多谱系人免疫重建 代表了研究HIV持续性的最先进的小动物模型之一， 发病机制我们和其他人已经表明，BLT小鼠模型可以有效地感染HIV， 在静止的CD 4 + T细胞中形成真实的整合后潜伏期。病毒载量可以抑制临床使用 相关的ART药物，如果ART停止，那么病毒载量迅速反弹。我们进一步推进了这一点， 通过利用表型中性、遗传多样性条形码化的HIV群来执行感染的模型。 这使得一个潜在的水库，以形成不同的基因标记的病毒。反弹可以 通过监测病毒载量来跟踪，以测试病毒重新出现的时间和程度， 血浆或组织，并对反弹的病毒进行深度测序，以定量单个条形码化的病毒的数量。 导致反弹的变体。这种综合方法将提供一个前所未有的艾滋病毒观点 储层形成和病毒反弹。在项目1中，我们将使用这个模型来确定前的贡献， ART感染至自发病毒反弹的时间（目的1），测试是否存在常见的生理/药理学 刺激改变反弹的频率（目标2），并量化结构化治疗中断（STI）的影响 关于潜在艾滋病毒储存库的规模和多样性（目标3）。总之，这些研究将测试关键，临床 相关参数，以确定它们如何影响停止ART后艾滋病毒的反弹，并将评估 允许反弹发生的后果。这将提供新的见解的机制，有助于 艾滋病毒反弹。