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/摘要 抗逆转录病毒疗法（ART）有效地控制了HIV复制，但这不是治愈方法。因此，很大 加强是致力于制定治疗方案，以减少病毒储存剂并增强抗病毒免疫力。 这些干预措施旨在允许艾滋病毒（PWH）的人停止艺术和耐用的控制艾滋病毒 持续无艺术的缓解。但是，无艺术缓解的病毒学和免疫学决定者 知之甚少。 HIV治疗研究的持久问题之一是干预必须多远 减少病毒储存库，以达到与临床相关的无艺术缓解时期。艺术品的储层尺寸 预计终止会影响病毒反弹的时间（TTR）和抗病毒免疫的能力 对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。然而，这是一个挑战 由于患者群体的可变性和困难，在人类临床试验中解决这些基本问题 在体内量化非常小的病毒储存库。结果，已经开发了数学模型 帮助指导和解释HIV治疗研究。这些模型同意，病毒库极小 对于艾滋病毒的缓解至关重要，但在如何实现缓解方面有所不同。 为了解决这些持久的问题，我们开发了一种猿猴免疫缺陷病毒（SIV）/恒河猴 猕猴模型精确设置了体内潜在储层的大小。为此，我们注入了定义的数字 自体内体外产生的SIV潜在地感染细胞成具有ART处理的SIV，不含Siv的恒河猕猴。这 模型提供了储层大小的精度和一致性，对于其他SIV模型很难 匹配。此外，建立具有一般条形码SIV的储层允许停止艺术并确定 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 确定在存在或不存在的情况下逐渐较小的SIV储存库影响TTR和PTC 抗病毒免疫。 具体目标1：确定定义的SIV病毒储存库的TTR。这个目标的目的是确定 在没有抗病毒免疫史的情况下，TTR的病毒储量越来越小。 具体目标2：确定病毒储层大小和抗病毒免疫对TTR和PTC的影响。这 该目标的目标是确定潜在储层大小是否影响抗病毒免疫控制的能力 治疗中断后的感染。