In vivo imaging of synaptic density in virally suppressed HIV-1 infection using 11CUCB-J PET

与全球3700万艾滋病毒携带者(PLWH)相关的最紧迫的神经学优先事项是 病毒抑制联合抗逆转录病毒治疗期间中枢神经系统(CNS)功能障碍的原因 治疗(CART)和纠正它们的干预。我们对艾滋病毒生物学基础的认识上的差距 CART中相关的神经认知障碍(手)阻碍了改善神经认知的进展 长期存活的PLWH的损害。 20多年前，在尸检标本中，突触密度降低被认为是主要的病理。 来自感染艾滋病毒的捐赠者，死亡时有轻微的认知障碍。密度的降低 突触素免疫反应终末在早期损害中被发现，在缺乏经典的 艾滋病毒脑炎的发现。这些令人信服的发现为随后的重要临床前研究奠定了基础 体外和动物研究揭示了对HIV中突触密度降低的进一步了解，包括局部 脆弱性、促成机制和可能的干预措施。然而，对这些调查结果的确认和 到目前为止，还不可能对活着的、由于缺乏接触到病毒而受到病毒抑制的人类进行进一步的研究 脑组织样本。此外，与坦率的神经元丢失不同，突触树突损伤可能是可逆的。因此， 在活人中检测突触密度下降并识别潜在机制的能力 与其存在的相关性将指导治疗方法，并为监测提供关键的生物标志物 减少艾滋病毒患者脑功能障碍的新疗法的效果。 此应用程序利用了最近前所未有的成像技术扩展，以应用 通过临床前研究获得对活体人类突触密度研究的理解。我们最近做了 开发了一种新的放射性示踪剂11C-UCB-J，用于使用正电子成像人脑中的突触密度- 发射断层扫描(PET)。在拟议的研究中，我们将把这一突破性的方法应用于 探讨在死后人类样本和动物模型中观察到的突触密度降低 将被发现生活在艾滋病毒复制被抑制的PLWH中。进一步的探索性研究将调查两者之间的联系 突触密度与临床前研究所涉及的实验室和临床指标之间的关系，包括 全身和中枢神经系统免疫激活和阿片类药物使用史。我们的初步研究验证了这种方式作为一种手段 检测CART治疗的HIV中异常的突触密度将产生重大影响，为未来奠定基础 研究突触密度与手部临床预后的关系，并提供治疗靶点和 旨在改善中枢神经系统艾滋病毒相关损伤的治疗研究的生物标记物。

The most pressing neurologic priorities relevant to the 37 million people living with HIV (PLWH) worldwide are to identify causes of central nervous system (CNS) dysfunction during virally suppressive combination antiretroviral therapy (cART) and interventions to correct them. Gaps in our understanding of the biological basis of HIV associated neurocognitive disorder (HAND) during cART impede progress in ameliorating neurocognitive impairment in long-term surviving PLWH. More than 20 years ago, reduced synaptic density was recognized as the primary pathology in autopsy specimens from HIV infected donors with mild forms of cognitive impairment at the time of death. Reduction in density of synaptophysin-immunoreactive terminals was identified in early stage impairment, in the absence of classical findings of HIV encephalitis. These compelling findings set the groundwork for subsequent important preclinical in vitro and animal studies revealing further understanding of reduced synaptic density in HIV, including regional vulnerability, contributory mechanisms, and potential interventions. However, confirmation of these findings and further investigation has not been possible to date in living, virologically suppressed humans due to lack of access to brain tissue samples. Additionally, unlike frank neuronal loss, synaptodendritic injury may be reversible. Thus, the ability to detect decreases in synaptic density in living humans and to identify potential mechanisms that correlate to its presence would guide therapeutic approaches and provide a critical biomarker for monitoring effects of novel therapeutics to reduce brain dysfunction in HIV. This application capitalizes on recent unprecedented expansion of imaging technologies to apply the understanding gained by pre-clinical studies to investigation of synaptic density in living humans. We have recently developed a novel radiotracer, 11C—UCB—J, for imaging synaptic density in the human brain using positron- emission tomography (PET). In the proposed research studies, we will apply this breakthrough methodology to explore whether observations of decreased synaptic density in postmortem human samples and animal models will be found living PLWH with suppressed HIV replication. Further exploratory studies will investigate associations between synaptic density and laboratory and clinical measures implicated by preclinical studies, including levels of systemic and CNS immune activation and history of opioid use. Our pilot study validating this modality as a means to detect aberrant synaptic density in cART-treated HIV will have a major impact, setting the stage for future studies of the relationship of synaptic density to clinical outcomes of HAND, and providing a therapeutic target and a biomarker for treatment studies aimed to improve HIV-related injury in the CNS.