In Vivo PET Imaging of HIV Infection

总结/摘要 根除艾滋病毒的一个主要障碍是感染细胞的存在，尽管受到抑制， 抗逆转录病毒疗法（ART）。HIV主要存在于外周循环之外，因此， 具有窝藏HIV能力的解剖和淋巴区室是常规方法无法接近的， 取样.迫切需要新的、非侵入性的体内方法来解决这一基本差距， 知识我们最近完成了临床前开发、动物试验和首次人体PET- 89 Zr-VRC 01的磁共振（MR）成像研究。在15名参与者的试点可行性研究中，我们 观察到在HIV感染者的各种淋巴和其他组织中89 Zr-VRC 01摄取显著增加， 与未感染的对照组相比，可检测到病毒血症和抑制性ART的个体。重要的是，PET 接受淋巴结转移的病毒血症和ART抑制受试者的腹股沟淋巴结中的示踪剂摄取 取样与直接在细胞中测量的HIV蛋白表达显著正相关。这些 令人兴奋的数据表明，艾滋病毒储库的PET成像有可能推动艾滋病毒领域的发展 治疗策略我们的目标是确定HIV感染的解剖位置和时间动力学 在病毒血症和ART抑制的个人，并验证示踪剂的吸收与艾滋病毒感染的真实措施。 我们将研究ART前后以及单独资助、高度监测的 治疗中断方案，该方案将在我们拟定研究的第一年开始开始招募。在整个 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）， 将HIV储库的这些组织评估与通过PET-MR成像的总89 Zr-VRC 01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关系。这种独特 PET技术具有任何现有人体扫描仪的最高灵敏度，这可能会被证明是至关重要的。 我们最近完成了EXPLORER， 对两名艾滋病毒感染者进行成像，显示图像分辨率和信号/噪声显着增加 比率。我们假设使用89 Zr-VRC 01与EXPLORER平台联合进行PET-MR成像 将提供组织范围储库的可量化的非侵入性测量，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（ART-1）中的89 Zr-VRC 01 PET活性。 抑制的，HIV控制者，病毒血症）和匹配的未感染对照，（1b）比较治疗前的89 Zr-VRC 01摄取 以及（1c）确定PET信号与HIV的组织测量之间的相关性 （2）确定超灵敏EXPLORER平台是否会增加89 Zr-VRC 01 PET的能力 影像学检查，以检测ART抑制个体中持续存在的HIV;（3）确定HIV的解剖学病灶 使用89 Zr-VRC 01 PET、PET-MR和EXPLORER平台，在ATI期间复发。

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.