In Vivo PET Imaging of HIV Infection

HIV 感染的体内 PET 成像

• 批准号: 10095057
• 负责人: Timothy Jensen Henrich
• 金额: $ 73.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-12 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10095057
• 关键词: Address; Adult; Anatomy; Animal Testing; Biopsy Specimen; Blood; Blood Circulation; Blood specimen; Bone Marrow; Cells; Collaborations; Collection; Data; Development; Enrollment; Feasibility Studies; Funding; Genetic Transcription; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Heterogeneity; Human; Image; ImmunoPET; Individual; Infection; Inguinal lymph node group; Interruption; Knowledge; Location; Lymphoid; Magnetic Resonance; Magnetic Resonance Imaging; Measurable; Measures; Methods; Monitor; Monoclonal Antibodies; Noise; Nucleic Acids; Participant; Peripheral; Positron-Emission Tomography; Production; Proteins; Protocols documentation; Radiolabeled; Recrudescences; Research; Residual state; Resolution; SIV; Sampling; Signal Transduction; Techniques; Technology; Tissue Sample; Tissues; Tracer; Viral; Viral Physiology; Viral Proteins; Viremia; Visualization; antiretroviral therapy; base; cohort; first-in-human; imaging approach; imaging program; imaging study; improved; in vivo; insight; lymph nodes; novel; novel strategies; preclinical development; programs; protein expression; tool; uptake; viral rebound

SUMMARY/ABSTRACT A major obstacle to HIV eradication is the presence of infected cells that persist despite suppressive antiretroviral therapy (ART). HIV largely resides outside of the peripheral circulation, and thus, numerous anatomical and lymphoid compartments that have the capacity to harbor HIV are inaccessible to routine sampling. Novel, non-invasive, in vivo methods are urgently needed to address this fundamental gap in knowledge. We recently completed the pre-clinical development, animal testing, and first-in-human PET- magnetic resonance (MR) imaging studies of 89Zr-VRC01. In a pilot feasibility study of 15 participants, we observed significantly increased 89Zr-VRC01 uptake in various lymphoid and other tissues in HIV-infected individuals with detectable viremia and on suppressive ART compared to uninfected controls. Importantly, PET tracer uptake in inguinal lymph nodes in viremic and ART-suppressed participants who underwent lymph node sampling significantly and positively correlated with HIV protein expression measured directly in cells. These exciting data suggest the PET imaging of the HIV reservoir has the potential to advance the field of HIV curative strategies. Our goals are to determine the anatomical location and temporal dynamics of HIV infection in viremic and ART-suppressed individuals and validate the tracer uptake with true measures of HIV infection. We will study location and dynamics before and after ART and during a separately funded, highly monitored treatment interruption protocol which will begin enrolling during the first year of our proposed study. Throughout these studies, we will simultaneously measure the reservoir directly (using lymph node and gut samples) and compare these tissue assessments of the HIV reservoir to the total 89Zr-VRC01 uptake by PET-MR imaging. We have established close collaborations with the EXPLORER imaging program at UC Davis. This unique PET technology has the highest sensitivity of any existing human scanner which will likely prove to be critically important in imaging HIV reservoirs among individuals on long-term ART. We recently completed EXPLORER imaging in two HIV-infected individuals and show dramatic increases in image resolution and signal/noise ratios. We hypothesize that PET-MR imaging using 89Zr-VRC01 in conjunction with the EXPLORER platform will provide a quantifiable, non-invasive measure of tissue-wide reservoirs and will identify anatomical foci of HIV recrudescence. Our aims are to: (1a) quantify 89Zr-VRC01 PET activity in HIV-infected participants (ART- suppressed, HIV controller, viremic) and matched uninfected controls, (1b) compare 89Zr-VRC01 uptake before and after initiation of ART, and (1c) determine the correlation between PET signal and tissue measures of HIV burden, (2) determine if the ultra-sensitive EXPLORER platform will increase the ability of 89Zr-VRC01 PET imaging to detect persistent HIV in ART-suppressed individuals, and, (3) determine the anatomical foci of HIV recrudescence during ATI using the 89Zr-VRC01 PET, PET-MR, and EXPLORER platforms.

摘要/摘要 根除艾滋病毒的一个主要障碍是受感染细胞的存在，尽管受到抑制，但它们仍然存在 抗逆转录病毒治疗（ART）。 HIV 大部分存在于外周循环之外，因此，许多 具有藏匿艾滋病毒能力的解剖学和淋巴室是常规无法进入的 采样。迫切需要新颖的、非侵入性的体内方法来解决这一根本差距 知识。我们最近完成了临床前开发、动物测试和首次人体 PET- 89Zr-VRC01 的磁共振 (MR) 成像研究。在 15 名参与者参与的试点可行性研究中，我们 观察到 HIV 感染者的各种淋巴组织和其他组织中 89Zr-VRC01 的摄取显着增加 与未感染的对照相比，具有可检测到的病毒血症且接受抑制性 ART 的个体。重要的是，PET 接受淋巴结转移的病毒血症和 ART 抑制参与者的腹股沟淋巴结示踪剂摄取 采样与直接在细胞中测量的 HIV 蛋白表达显着呈正相关。这些 令人兴奋的数据表明 HIV 储存库的 PET 成像有可能推动 HIV 领域的发展 治疗策略。我们的目标是确定 HIV 感染的解剖位置和时间动态 在病毒血症和 ART 抑制的个体中进行检测，并通过 HIV 感染的真实测量来验证示踪剂的摄取。 我们将研究 ART 前后以及在单独资助、高度监控的过程中的位置和动态 治疗中断方案将在我们拟议研究的第一年开始招募。自始至终 在这些研究中，我们将同时直接测量储库（使用淋巴结和肠道样本）并 通过 PET-MR 成像将 HIV 储存库的这些组织评估与 89Zr-VRC01 的总摄取进行比较。 我们与加州大学戴维斯分校的 EXPLORER 成像项目建立了密切的合作。这种独特的 PET 技术具有所有现有人体扫描仪中最高的灵敏度，这可能会被证明是至关重要的 对于长期接受 ART 的个体中 HIV 病毒库的成像非常重要。我们最近完成了 EXPLORER 对两名 HIV 感染者进行成像，结果显示图像分辨率和信号/噪声显着增加 比率。我们假设使用 89Zr-VRC01 结合 EXPLORER 平台进行 PET-MR 成像 将提供组织范围内储库的可量化、非侵入性测量，并确定 艾滋病毒复发。我们的目标是：(1a) 量化 HIV 感染参与者中的 89Zr-VRC01 PET 活性（ART- 抑制、HIV 控制者、病毒血症）和匹配的未感染对照，(1b) 比较之前的 89Zr-VRC01 摄取 并在开始 ART 后，(1c) 确定 PET 信号与 HIV 组织测量值之间的相关性 (2)确定超灵敏EXPLORER平台是否会增加89Zr-VRC01 PET的能力 成像以检测 ART 抑制个体中持续存在的 HIV，并且，(3) 确定 HIV 的解剖灶 使用 89Zr-VRC01 PET、PET-MR 和 EXPLORER 平台在 ATI 期间进行复发。