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 HIV/AIDS 研究领域开始努力治愈 HIV-1 感染，深入了解 HIV-1 病毒的储存库 面对抑制性抗逆转录病毒治疗（ART），维持病毒持续存在至关重要。 一直致力于使用循环 CD4+ T 细胞来表征原病毒和病毒生长测定 (VOA) 其了解组织中储存库性质的能力可能有限，更重要的是，了解其起源的能力可能有限 此外，这些方法并没有揭示 ART 中断后病毒复发的情况。 非 CD4+ T 细胞（例如组织巨噬细胞）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组成可能反映了病毒血症储存库的性质 项目 3 将评估病毒库的起源和宿主抗病毒免疫力的质量。 治疗中断前的活动，以及反弹的病毒血症的成分，以获得 深入了解宿主抗病毒免疫影响病毒反弹活动的病毒学机制。 项目 1 将提供已完成和计划中的人类治疗性疫苗试验的纵向样本（BCN ATI、RISVAC03、BCN02 和 AELIX003）将纵向提供 SIV 猕猴模型（项目 2）。 治疗后从 ART 抑制、接种 RhCMVd10/SIV 的猕猴身上采集血液和组织样本 至关重要的是，这两个项目都允许最早对反弹的病毒血症进行采样，这最有可能发生。 反映其起源于在 ART 抑制下持续存在的储存库。 我们致力于通过 RhCMVd10/SIV 疫苗接种在猕猴和人类中引发免疫反应 通过病毒载量“数据通知”疫苗，影响病毒库活性，这通过对 为了验证这一假设，我们研究了病毒反弹的时间以及病毒库的活性和组成。 提出以下具体目标： 目标是 (i) 评估治疗性疫苗接种对病毒库活性的影响，(ii) 评估 治疗性疫苗接种对反弹病毒组成的影响，以及（iii）确定巨噬细胞是否 病毒血症反弹中存在的热带病毒具有巨噬细胞起源。