HIV Tropism, Persistence, Inflammation and Neurocognition in Therapy Initiation

描述（由申请人提供）：联合抗逆转录病毒治疗的可用性大大减少了HIV相关痴呆，但神经认知功能障碍仍可能在病程早期发生（统称为HAND的病症），并且对早期障碍改善、持续或甚至在治疗时恢复的程度知之甚少。此外，虽然已知HIV可在CNS中发现并在CSF中采样，但CNS中病毒复制作为损害的贡献或原因的作用尚不清楚。最后，在治疗期间成功抑制血液中的病毒并不总是伴随着CNS中的抑制，这种明显的病毒复制是治疗期间缺乏损伤消退的潜在促成因素。在本申请中，五位资深研究人员提出了三个相互关联的项目，以研究在抗病毒治疗的背景下CNS中病毒复制的问题。我们相信这些研究将提供有关神经认知障碍基础的基本机制信息，这些信息在设计有效的干预措施之前是必要的。该提议基于一个观察性队列，该队列中的受试者开始治疗，从入组到抑制血液中的病毒，纵向采集血液和CSF样本。项目1将重点关注病毒进入时在CNS中复制的证据，以及这种病毒的向性（即它是在活化的T细胞中复制还是在巨噬细胞/小胶质细胞中复制）。项目2将检查免疫介导的炎症水平，以及入组时神经元损伤的证据及其在治疗开始时的消退。还将进行神经精神评估，以确定神经认知障碍的相关性以及治疗后神经认知障碍消退或持续的预测因素。项目3将解决成功治疗时CNS中持续病毒复制的问题，包括定义持续病毒的嗜性、CNS中治疗选择和药物水平的作用，以及参与从CNS泵送药物以影响药物浓度的蛋白质中遗传多态性的可能性，从而允许残留的持续病毒复制。总的来说，这些研究将带来对病毒复制和病毒进化的详细了解，以及随之而来的炎症和神经元损伤问题，

DESCRIPTION (provided by applicant): The availability of combination antiretroviral therapy has greatly reduced HIV-associated dementia but neurocognitive impairment can still occur earlier in the disease course (conditions collectively known as HAND), and the extent to which earlier impairment improves, persists, or even worsens when on therapy is poorly understood. Also, while it is known that HIV can be found in the CNS and sampled in the CSF, the role of viral replication in the CNS as being contributing or causal to impairment is unknown. Finally, successful suppression of virus in the blood while on therapy is not always accompanied by suppression in the CNS, with this apparent viral replication being a potential contributing factor to a lack of resolution of impairment while on therapy. In this application five senior investigators propose three inter-related projects to study issues surrounding viral replication in the CNS in the setting of antiviral therapy. We believe these studies will provide essential mechanistic information regarding the basis for neurocognitive impairment and that this information is necessary before effective interventions can be designed. The proposal is based on an observational cohort of subjects initiating therapy with longitudinal sampling of blood and CSF from entry through suppression of virus in the blood. Project 1 will focus on evidence of viral replication in the CNS at the time of entry, and on the tropism of this virus (i.e. is it replicating in activated T cells or in macrophage/microglia cells). Project 2 will examine the level of immune-mediated inflammation, and evidence for neuronal damage at entry and their resolution with the initiation on therapy. Neuropsychiatric evaluations will also be done to determine the correlates of neurocogntive impairment and the predictors of it resolution or persistence on therapy. Project 3 will address the issue of persistent viral replication in the CNS while on successful therapy, including defining the tropism of the persisting virus, the role of therapy choice and drug levels in the CNS, and the potential for genetic polymorphism in proteins involved in pumping drugs from the CNS to impact drug concentrations to such an extent as to allow residual, ongoing viral replication. Collectively, these studies will bring a detailed understanding of viral replication and viral evolution, with the attendant issues of inflammation and neuronal damage,