Central Nervous System Events in Primary HIV Infection

描述（由申请人提供）：候选人的长期目标是了解，然后预防或治疗，HIV在中枢神经系统（CNS）中的破坏性影响的机制。拟议的研究重点是原发性HIV感染期间CNS中的事件，定义为最初获得病毒后的前六个月。HIV在感染的最早阶段进入CNS，并且在慢性感染期间，CNS是持续性病毒感染的部位。该提案的基本假设是，HIV的早期神经侵入涉及宿主免疫激活环境中的病毒运输，并允许建立持续和区室化的CNS感染。候选人将在原发性感染期间以及治疗开始和中断期间对个体进行系列横断面评价，以纵向定义CNS宿主反应和脑脊液（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物、CSF细胞和炎症变化以及神经行为指数，证明免疫激活、炎症和组织损伤的宿主CNS反应的自然史。第二个目的是比较CSF和血浆中病毒载量和病毒群体的分子特征，包括基因型和表型耐药性、趋化因子受体利用率和克隆分析，以证明区室化感染的早期建立。最终目的是使用上述技术，通过对因独立于本建议的原因开始治疗的个体进行横断面、系列研究，确定抗逆转录病毒治疗对CNS原发性HIV病程的影响。确定原发性HIV感染是建立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HIV CNS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促进复杂和负责任的调查。神经科的临床服务将包括艾滋病患者以及其他传染病患者的护理。Price，Meyerhoff和Hecht的指导以及UCSF神经病学部门的支持将使申请人成为学术界的一员。

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.