Central Nervous System Events in Primary HIV Infection

描述(由申请者提供)：应聘者的长期目标是了解、然后预防或治疗艾滋病毒对中枢神经系统(CNS)的破坏性影响的潜在机制。拟议的研究重点是在初次感染艾滋病毒期间中枢神经系统发生的事件，定义为首次感染病毒后的头六个月。艾滋病毒在感染的最早阶段进入中枢神经系统，而在慢性感染期间，中枢神经系统是持续病毒感染的场所。该建议的基本假设是，艾滋病毒早期神经侵袭涉及宿主免疫激活背景下的病毒贩运，并允许建立持续性和区隔的中枢神经系统感染。候选人将对初次感染期间以及治疗开始和中断期间的个体进行一系列横断面评估，以纵向确定中枢神经系统宿主的反应和脑脊液(CSF)HIV人群的特征。第一个目的是通过高场(4特斯拉)磁共振波谱测量脑代谢产物、脑脊液细胞和炎症变化以及神经行为指数来揭示宿主中枢神经系统免疫激活、炎症和组织损伤的自然历史。第二个目的是比较脑脊液和血浆中的病毒载量和病毒群体的分子特征，包括基因和表型耐药性、趋化因子受体的利用和克隆分析，以证明早期建立分区感染。最终目的是使用上述技术，通过对出于与本提议无关的原因开始治疗的个人进行横断面系列研究，确定抗逆转录病毒治疗对中枢神经系统原发艾滋病毒病程的影响。确定原发HIV感染是确定CNS感染和损伤的关键时期，并揭示CNS治疗的早期效果，将深刻影响早期HIV的治疗策略。候选人的职业发展计划将使她能够将临床研究的观察结果转化为对艾滋病毒中枢神经系统并发症的更好理解和治疗。参加正式的临床研究高级培训计划将培养成熟和负责任的调查。神经科的临床服务将包括对艾滋病患者和其他感染性疾病患者的护理。最后，普莱斯博士、迈耶霍夫博士和赫克特博士的指导以及加州大学旧金山分校神经病学系的支持将使申请者作为学术界的一员脱颖而出。

DESCRIPTION (provided by applicant): The candidate's long-term goal is to understand, then prevent or treat, mechanisms underlying the damaging effects of HIV in the central nervous system (CNS). The proposed research focuses upon events in the CNS during primary HIV infection, defined as the first six months after initial acquisition of virus. HIV enters the CNS in the earliest stages of infection, and during chronic infection the CNS is a site of persistent viral infection. The underlying hypothesis of the proposal is that early neuroinvasion by HIV involves viral trafficking in the setting of host immune activation and allows the establishment of persistent and compartmentalized CNS infection. The candidate will use serial cross-sectional evaluations of individuals during primary infection and during initiation and interruption of therapy to longitudinally define CNS host responses and features of cerebrospinal fluid (CSF) HIV populations. The first aim is to demonstrate the natural history of host CNS responses of immune activation, inflammation and tissue injury through measurement of cerebral metabolites by high-field (4 Tesla) magnetic resonance spectroscopy, CSF cellular and inflammatory changes, and neurobehavioral indices. The second aim is to compare viral loads and molecular characteristics of viral populations between the CSF and plasma, including genotypic and phenotypic resistance, chemokine receptor utilization, and clonal analysis, to demonstrate early establishment of compartmentalized infection. The final aim is to use the above techniques to define the effects of treatment with antiretroviral therapy on the course of primary HIV in the CNS, through cross-sectional, serial studies of individuals initiating treatment for reasons independent of this proposal. Identification of primary HIV infection as a crucial period for establishment of CNS infection and injury and revealing the early effects of treatment in the CNS will profoundly influence treatment strategies in early HIV. The candidate's career development plan will allow her to translate observations from clinical research into improved understanding and treatment of CNS complications of HIV. Participation in a formal Advanced Training in Clinical Research program will foster sophisticated and responsible investigation. Clinical service in neurology will include care of patients with AIDS as well as those with other infectious conditions. Finally, the guidance of Drs. Price, Meyerhoff, and Hecht and support from UCSF's Neurology Department will allow the applicant to excel as an integral member of the academic community.