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)有效地控制了艾滋病毒的复制，但它不是治愈的方法。因此，相当大的 Effted致力于开发减少病毒库和提高抗病毒免疫力的治愈方案。 这些干预措施寻求允许艾滋病毒携带者(PWH)停止抗逆转录病毒治疗并持久地控制艾滋病毒，诱导 持续的无艺术性缓解。然而，无ART缓解的病毒学和免疫学决定因素 人们对此了解甚少。艾滋病毒治疗研究的一个长期问题是，干预措施必须走多远 减少病毒库，以达到临床相关的无ART缓解期。艺术中的水库大小 终止预计会影响病毒反弹的时间(TTR)和抗病毒免疫的能力 控制病毒复制的响应。然而，储油层大小和TTR之间的联系尚不清楚，而且 治疗后病毒控制(PTC)的免疫学基础尚不清楚。然而，要做到这一点很有挑战性 由于患者群体的多样性和难度，在人体临床试验中解决这些基本问题 在体内对极小的病毒储存库进行量化。因此，数学模型被开发为 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 对艾滋病毒缓解至关重要，但在如何实现缓解方面存在差异。 因此，为了解决这些长期存在的问题，我们开发了一种猴免疫缺陷病毒(SIV)/恒河猴 猕猴模型，精确设定体内潜伏水库的大小。为此，我们将定义数量的 体外自体产生的SIV潜伏感染细胞进入经过ART治疗的SIV幼稚恒河猴。这 模型提供了其他SIV模型难以达到的储集层大小的精度和一致性 火柴。此外，建立带有基因条形码SIV的水库允许停止ART并确定 TTR值和重新激活的病毒数量。因此，我们建议使用这个新的延迟模型来 确定在存在或不存在以下情况下，逐渐变小的SIV储油池对TTR和PTC的影响 抗病毒免疫。 具体目标1：确定已确定的SIV病毒库的TTR。此目标的目标是确定 在缺乏抗病毒免疫的情况下，TTR适用于越来越小的病毒库。 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。这个 这一目标的目的是确定潜伏的水库大小是否影响抗病毒免疫控制的能力。 治疗中断后感染。