Reservoir activity and recrudescent virus composition in HIV and SIV rebound

HIV 和 SIV 反弹中的病毒库活性和复发病毒组成

• 批准号: 10205971
• 负责人: Mario Stevenson
• 金额: $ 29.59万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-19 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205971
• 关键词: AIDS/HIV problem; Aftercare; Anatomy; Automobile Driving; B-Lymphocytes; Biological Assay; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell surface; Cells; Clinical Research; Data; Frequencies; HIV; HIV-1; Human; Immune; Immune response; Immunity; Individual; Infection; Interruption; Kinetics; Light; Lung; Lymphoid Tissue; Macaca; Modeling; Nature; Phylogenetic Analysis; Population; Proviruses; RNA; Research; Role; SIV; SIV Vaccines; Sampling; Shapes; Source; T cell response; T-Lymphocyte; Testing; Therapeutic Effect; Time; Tissues; Tropism; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Variant; Viral; Viral Load result; Viral reservoir; Viremia; Virus; antiretroviral therapy; antiviral immunity; digital; insight; lymph nodes; macrophage; preclinical study; predicting response; response; therapeutic vaccine; vaccine trial; viral RNA; viral rebound; virology

As the HIV/AIDS research field embarks on an endeavor to cure HIV-1 infection, insight into the reservoirs that sustain viral persistence in the face of suppressive antiretroviral therapy (ART) is essential. Most of the focus has been on characterization of proviruses and viral outgrowth assays (VOA) using circulating CD4+ T-cells that may have limited ability to inform on the nature of the reservoirs in tissues and more importantly, the origin of the viruses that recrudesce upon ART interruption. Furthermore, these approaches do not reveal the potential contribution of non-CD4+ T-cells, such as tissue macrophages, to viral persistence and rebound. The timing and composition of rebounding viremia is likely to reflect the nature of the reservoir from which it originated and the quality of host antiviral immunity levied against it. Project 3 will assess viral reservoir activity prior to treatment interruption, as well as the composition of rebounding viremia, to gain insight into the virologic mechanisms whereby host antiviral immunity impacts viral rebound activity. Project 1 will provide longitudinal samples from completed and planned human therapeutic vaccine trials (BCN ATI, RISVAC03, BCN02 and AELIX003). The SIV macaque model (Project 2) will provide longitudinally sampled blood and tissues from ART-suppressed, RhCMVd10/SIV-vaccinated macaques after treatment interruption. Crucially, both projects allow the earliest sampling of rebounding viremia, which is most likely to reflect its origins in the reservoirs that persist under ART suppression. We hypothesize that immune responses in macaques elicited by RhCMVd10/SIV vaccination and in humans by a viral load “data-informed” vaccine, impact viral reservoir activity and that this is manifest by an impact on time to viral rebound as well as activity and composition of the viral reservoir. To pursue this hypothesis, we propose the following specific aims: The objectives are to (i) evaluate the effect of therapeutic vaccination on viral reservoir activity, (ii) assess the effect of therapeutic vaccination on rebounding virus composition, and (iii) determine whether macrophage- tropic viruses present in rebounding viremia have a macrophage origin.

随着艾滋病毒/艾滋病研究领域开始奋进治愈HIV-1感染，深入了解 在抑制性抗逆转录病毒治疗（ART）面前，维持病毒持续存在是至关重要的。大部分的重点 一直在使用循环CD 4 + T细胞对前病毒和病毒生长测定（VOA）进行表征 这可能限制了了解组织中储库性质的能力，更重要的是， 在抗逆转录病毒治疗中断后复发的病毒。此外，这些方法并没有揭示 非CD 4 + T细胞（如组织巨噬细胞）对病毒持续存在和反弹的潜在贡献。 病毒血症反弹的时间和成分可能反映了它所来自的宿主的性质。 起源和宿主抗病毒免疫的质量。项目3将评估病毒库 治疗中断前的活性，以及反弹病毒血症的组成，以获得 深入了解宿主抗病毒免疫力影响病毒反弹活性的病毒学机制。 项目1将提供已完成和计划的人类治疗性疫苗试验（BCN）的纵向样本 ATI、RISVAC 03、BCN 02和AELIX 003）。SIV猕猴模型（项目2）将提供纵向 治疗后从ART抑制、RhCMVd 10/SIV接种的猕猴中采集血液和组织样本 中断.至关重要的是，这两个项目都允许对反弹的病毒血症进行最早的采样，这最有可能 反映了它的起源，在水库坚持抗逆转录病毒治疗抑制。 我们假设RhCMVd 10/SIV疫苗在猕猴和人类中引起的免疫应答 通过病毒载量“数据通知”疫苗，影响病毒库活性，这表现为对 病毒反弹的时间以及病毒库的活性和组成。为了实现这一假设，我们 提出以下具体目标： 目的是（i）评价治疗性疫苗接种对病毒储库活性的影响，（ii）评估 治疗性疫苗接种对反弹病毒组成的影响，和（iii）确定巨噬细胞- 存在于反弹病毒血症中的嗜性病毒具有巨噬细胞来源。