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/概要 抗逆转录病毒疗法（ART）有效地控制了艾滋病毒的复制，但它不是一种治愈方法。因此， 致力于开发治疗方案，减少病毒库和提高抗病毒免疫力。 这些干预措施旨在使艾滋病毒感染者（PWH）停止ART并持久控制艾滋病毒， 持续无ART缓解。然而，无ART缓解的病毒学和免疫学决定因素 我们对此知之甚少。艾滋病治疗研究的一个持久问题是，干预措施必须在多大程度上 减少病毒库，以达到临床相关的无ART缓解期。ART的水库规模 终止预期会影响病毒反弹时间（TTR）和抗病毒免疫能力。 控制病毒复制。然而，水库规模和TTR之间的关系是未知的， 治疗后病毒控制（PTC）的免疫学基础尚不清楚。然而，这是具有挑战性的， 由于患者群体的可变性和困难， 定量体内极小的病毒库。因此，已经开发了数学模型， 帮助指导和解释HIV治疗研究。这些模型一致认为，非常小的病毒库， 这是艾滋病毒缓解所必需的，但在如何实现缓解方面有所不同。 因此，为了解决这些持久的问题，我们开发了一种猴免疫缺陷病毒（SIV）/恒河猴 猕猴模型，精确地设定了体内潜在水库的大小。为此，我们注入一定数量的 自体体外产生的SIV潜伏感染的细胞植入ART处理的SIV未处理的恒河猴中。这 模型提供了一个精确度和一致性的油藏规模，这是其他SIV模型难以做到的。 匹配.此外，建立具有基因条形码化的SIV的储库允许停止ART并确定SIV的浓度。 TTR和再活化病毒的数量。因此，我们建议使用这种新的延迟模型， 确定在存在或不存在以下情况下，逐渐变小的SIV储库如何影响TTR和PTC： 抗病毒免疫 具体目标1：确定确定SIV病毒储库的TTR。本目标的目的是确定 在缺乏抗病毒免疫的情况下，TTR用于越来越小的病毒储库。 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。的 本研究的目的是确定潜在储库的大小是否影响抗病毒免疫的控制能力。 治疗中断后感染。