In Vivo PET Imaging of HIV Infection

摘要/摘要 根除艾滋病毒的一个主要障碍是感染细胞的存在，这些细胞尽管受到抑制，但仍然存在 抗逆转录病毒疗法(ART)。艾滋病毒主要存在于外周循环之外，因此有许多 有能力携带艾滋病毒的解剖和淋巴隔间是常规方法无法进入的 取样。迫切需要新的、非侵入性的活体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、动物试验和首例人类PET- 89Zr-VRC01的磁共振成像研究在一项由15名参与者参与的试验可行性研究中，我们 观察到HIV感染者不同淋巴和其他组织对89Zr-VRC01的摄取显著增加 可检测到的病毒血症和抑制ART的个体与未感染的对照组相比。重要的是，PET 接受淋巴清扫的病毒携带者和ART受抑者腹股沟淋巴结示踪剂摄取 采样与直接在细胞中测量的HIV蛋白表达显著正相关。这些 令人振奋的数据表明，对艾滋病毒储存库的PET成像具有推动艾滋病毒领域的潜力 治疗策略。我们的目标是确定艾滋病毒感染的解剖位置和时间动态 在病毒携带者和ART抑制的个体中，并用艾滋病毒感染的真实测量来验证示踪剂的摄取。 我们将研究ART前后的位置和动态，以及在单独资助、高度监控的 治疗中断方案，将在我们拟议研究的第一年开始登记。贯穿始终 在这些研究中，我们将同时直接测量储存库(使用淋巴和肠道样本)和 将这些对HIV储存库的组织评估与PET-MR成像中总的89Zr-VRC01摄取量进行比较。 我们与加州大学戴维斯分校的探索者成像项目建立了密切的合作关系。这个独一无二的 在任何现有的人类扫描仪中，宠物技术具有最高的灵敏度，这很可能被证明是至关重要的 对长期接受抗逆转录病毒治疗的个体中的艾滋病毒携带者进行成像很重要。我们最近完成了探险家 对两名HIV感染者进行了成像，并显示图像分辨率和信号/噪声显著增加 比率。我们假设使用89Zr-VRC01和EXPLORER平台进行的PET-MR成像 将提供一种可量化的、非侵入性的组织范围内储存物的测量方法，并将识别 艾滋病毒复发。我们的目标是：(1A)量化HIV感染参与者中的89Zr-VRC01PET活性(ART- 抑制、HIV控制者、病毒携带者)和匹配的未感染对照组，(1b)比较以前对89Zr-VRC01的摄取 在启动ART之后，以及(1c)确定PET信号与HIV组织测量之间的相关性 负荷，(2)确定超灵敏探测器平台是否会提高89Zr-VRC01PET的能力 成像以检测ART抑制的个体中的持久性艾滋病毒，以及，(3)确定艾滋病毒的解剖部位 使用89Zr-VRC01 PET、PET-MR和EXPLORER平台进行ATI期间的复发。

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.