The Neuropathobiology of Primary HIV-1 Infection

描述(由申请人提供)：拟议的研究集中在最初感染艾滋病毒后最初几周和几个月内中枢神经系统(CNS)发生的事件，统称为原发艾滋病毒感染(PHI)。艾滋病毒在感染的最早阶段进入中枢神经系统，而中枢神经系统在疾病的整个慢性阶段都是持续病毒感染的场所。这一设想的基本假设是，最初的病毒神经侵袭在HIV的神经发病机制中起重要作用，导致CNS持续和分区感染的基础，并启动脑损伤的过程。研究人员将对75名在PHI期间出现的受试者进行纵向研究，以研究宿主免疫和神经反应的过程以及在此期间开始的脑脊液(CSF)HIV准种的特征。第一个目的是通过测量炎症、免疫反应和神经元损伤的脑脊液标志物、高场(4特斯拉)磁共振波谱和神经心理测试来了解病毒负荷、早期宿主炎症和中枢神经系统组织损伤之间的关系。第二个目的是通过异源双链追踪法检测脑脊液和血浆中HIV准种序列的差异，并通过测量病毒复制能力和辅助受体利用来确定每个区段中早期HIV物种的特征，从而建立CNS感染的区划。最终目的是描述PHI期间开始的抗逆转录病毒治疗对中枢神经系统炎症和神经反应的影响。这项研究建立了一个长期随访的队列和一个储存库的纵向样本库，用于未来的研究。我们提出的方法将提供有关早期HIV在神经系统中的临床重要性的关键信息；如果在PHI期间发生免疫激活介导的脑损伤或建立分区的CNS感染，早期使用免疫调节或抗逆转录病毒药物可能提供以前未被认识到的长期神经保护。同样，在PHI期间检测治疗对中枢神经系统的有益影响有可能深刻影响早期HIV的治疗策略。这项提案的总体目标是通过提高对艾滋病毒在神经系统中的早期影响和治疗的了解，改善或预防艾滋病毒相关的中枢神经系统损害。中枢神经系统(CNS)损伤仍然是HIV-1感染的主要并发症，并有可能影响全球4000万HIV-1感染者中至少20%的人。阐明中枢神经系统感染和神经损伤的时间进程将有助于理解HIV-1感染的早期阶段在艾滋病神经发病机制中的意义。此外，揭示中枢神经系统抗逆转录病毒治疗的早期效果可能为在早期HIV-1感染中启动抗逆转录病毒治疗提供新的理论基础。

DESCRIPTION (provided by applicant): The proposed research focuses upon events in the central nervous system (CNS) during the earliest weeks and months after initial acquisition of HIV infection, collectively defined as primary HIV infection (PHI). HIV enters the CNS in the earliest stages of infection, and the CNS is a site of persistent viral infection throughout the chronic stages of disease. The underlying hypothesis of this proposal is that initial viral neuroinvasion is important in the neuropathogenesis of HIV, leading to the foundation of persistent and compartmentalized CNS infection, and initiating the process of brain injury. The investigators will longitudinally study 75 subjects presenting during PHI to study the course of host immune and neurological responses and features of cerebrospinal fluid (CSF) HIV quasispecies beginning during this period. The first aim is to understand the relationship between viral burden, early host inflammation, and tissue injury in the CNS, through measurement of CSF markers of inflammation, immune response, and neuronal injury, cerebral metabolites by high-field (4 Tesla) magnetic resonance spectroscopy, and neuropsychological testing. The second aim is to investigate the establishment of compartmentalized CNS infection through use of the heteroduplex tracking assay to detect HIV quasispecies sequence differences between and within CSF and plasma, and through measurement of viral replicative capacity and coreceptor utilization to define the character of early HIV species in each compartment. The final aim is to describe the effect of antiretroviral therapy initiated during PHI on the course of CNS inflammation and neurological responses. This study establishes a cohort for extended follow-up and a repository of banked longitudinal samples for future studies. Our proposed approach will provide crucial information about the clinical importance of early HIV in the nervous system; if immunoactivation-mediated brain injury or the establishment of compartmentalized CNS infection occurs during PHI, early treatment with immune- modulating or antiretroviral medications may provide previously unrecognized long-term neuroprotection. Similarly, detection of beneficial effects of treatment on the CNS during PHI has the potential to profoundly influence treatment strategies in early HIV. The overall goal of this proposal is to ameliorate or prevent HIV-related CNS damage through improved understanding of the early effects and treatment of HIV in the nervous system. Central nervous system (CNS) impairment remains a major complication of HIV-1 infection, and has the potential to affect at least 20% of the 40 million people worldwide who are living with HIV-1. Clarification of the time course of establishment of CNS infection and neurological injury will contribute to an understanding of the significance of the earliest stages of HIV-1 infection in the neuropathogenesis of AIDS. In addition, revealing the early effects of antiretroviral treatment in the CNS may provide a new rationale for initiating antiretroviral therapy in early HIV-1 infection.