Determining the impact of ultra-small SIV reservoirs on sustained ART-free remission

确定超小型 SIV 储库对持续无 ART 缓解的影响

• 批准号: 10792978
• 负责人: Matthew R. Reynolds
• 金额: $ 32.34万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-10 至 2023-08-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10792978
• 关键词: Address; Affect; Aftercare; Agreement; Autologous; Bar Codes; Cells; Clinical; Clinical Trials; Cytotoxic T-Lymphocytes; Disease remission; Event; Goals; HIV; Human; Immune response; Immunologics; In Vitro; Infection Control; Interruption; Intervention; Length; Macaca mulatta; Modeling; Monkeys; Patients; Persons; Plasma; Recombinants; Regimen; Research; Research Priority; SIV; Slide; Testing; Time; United States National Institutes of Health; Viral; Viral Load result; Viral reservoir; Viremia; Virus; Virus Latency; Virus Replication; antiretroviral therapy; antiviral immunity; clinically relevant; in vivo; mathematical model; novel; predictive marker; predictive modeling; reactivation from latency; therapy development; tool; viral rebound

Abstract/Summary Antiretroviral therapy (ART) effectively controls HIV replication, but it is not a cure. Therefore, considerable efforted is devoted to developing cure regimens that reduce viral reservoirs and boost antiviral immunity. These interventions seek to permit people with HIV (PWH) to stop ART and durably control HIV, inducing sustained ART-free remission. However, the virologic and immunologic determinants of ART-free remission are poorly understood. One of the enduring questions for HIV cure research is how far interventions must reduce viral reservoirs to attain clinically relevant periods of ART-free remission. The reservoir size at ART termination is anticipated to affect the time to viral rebound (TTR) and the capacity of antiviral immune responses to control virus replication. Yet, the association between reservoir size and TTR is unknown, and the immunologic basis of post-treatment viral control (PTC) is unclear. Nevertheless, it is challenging to address these fundamental questions in human clinical trials due to variability in patient groups and difficulty quantifying extremely small viral reservoirs in vivo. As a result, mathematical models have been developed to help guide and interpret HIV cure studies. These models agree that extremely small viral reservoirs are essential for HIV remission but differ in how remission can be achieved. Thus, to address these enduring questions, we developed a simian immunodeficiency virus (SIV)/rhesus macaque model that precisely sets the size of latent reservoirs in vivo. To do so, we infuse defined numbers of autologous in vitro generated SIV latently infected cells into ART-treated, SIV-naïve rhesus macaques. This model provides a level of precision and consistency in reservoir sizes that is difficult for other SIV models to match. Further, establishing reservoirs with genetically barcoded SIV permits stopping ART and determining TTR and the number of reactivating viruses. Therefore, we propose using this novel latency model to determine how progressively smaller SIV reservoirs affect TTR and PTC in the presence or absence of antiviral immunity. Specific Aim 1: Determine the TTR for defined SIV viral reservoirs. The goal of this Aim is to determine the TTR for increasingly small viral reservoirs in the absence of antiviral immunity. Specific Aim 2: Determine the impact of viral reservoir size and antiviral immunity on TTR and PTC. The goal of this Aim is to determine if latent reservoir size affects the ability of antiviral immunity to control infection after treatment interruption.

摘要/总结 抗逆转录病毒疗法 (ART) 可以有效控制 HIV 复制，但它并不是治愈方法。因此，相当 努力致力于开发减少病毒储存和增强抗病毒免疫力的治疗方案。 这些干预措施旨在让艾滋病毒感染者 (PWH) 停止抗逆转录病毒治疗并持久控制艾滋病毒，从而诱导 持续无 ART 缓解。然而，无 ART 缓解的病毒学和免疫学决定因素 人们了解甚少。艾滋病毒治疗研究的持久问题之一是干预措施必须达到何种程度 减少病毒储存，以达到临床相关的无 ART 缓解期。 ART 时的储液器尺寸 预计终止会影响病毒反弹时间（TTR）和抗病毒免疫能力 控制病毒复制的反应。然而，储层大小和 TTR 之间的关联尚不清楚，并且 治疗后病毒控制（PTC）的免疫学基础尚不清楚。尽管如此，仍具有挑战性 由于患者群体的差异和困难，解决人体临床试验中的这些基本问题 量化体内极小的病毒库。结果，数学模型被开发出来 帮助指导和解释艾滋病毒治愈研究。这些模型一致认为，极小的病毒库是 对于艾滋病毒缓解至关重要，但如何实现缓解有所不同。 因此，为了解决这些长期存在的问题，我们开发了猿猴免疫缺陷病毒（SIV）/恒河猴 精确设定体内潜在储库大小的猕猴模型。为此，我们注入了一定数量的 自体体外产生的 SIV 潜伏感染细胞进入经过 ART 处理、未接触过 SIV 的恒河猴。这 模型提供了储层尺寸的精确度和一致性，这是其他 SIV 模型难以做到的 匹配。此外，建立带有基因条形码 SIV 的储存库可以停止 ART 并确定 TTR 和重新激活病毒的数量。因此，我们建议使用这种新颖的延迟模型来 确定在存在或不存在的情况下，逐渐变小的 SIV 储库如何影响 TTR 和 PTC 抗病毒免疫力。 具体目标 1：确定特定 SIV 病毒储存库的 TTR。该目标的目标是确定 在缺乏抗病毒免疫力的情况下，针对越来越小的病毒库进行 TTR。 具体目标 2：确定病毒库大小和抗病毒免疫对 TTR 和 PTC 的影响。这 该目的的目标是确定潜伏病毒库大小是否影响抗病毒免疫控制的能力 治疗中断后感染。