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）中破坏性影响的潜在机制。拟议的研究侧重于原发性HIV感染期间的中枢神经系统事件，定义为首次获得病毒后的前六个月。HIV在感染的早期阶段进入中枢神经系统，在慢性感染期间，中枢神经系统是一个持续病毒感染的部位。该提议的潜在假设是，早期的神经入侵涉及到HIV病毒在宿主免疫激活的背景下的贩运，并允许建立持续和分区的中枢神经系统感染。该候选人将在初次感染期间以及治疗开始和中断期间对个体进行连续横断面评估，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、脑脊液细胞和炎症变化以及神经行为指标，揭示宿主CNS免疫激活、炎症和组织损伤反应的自然历史。第二个目的是比较脑脊液和血浆之间的病毒载量和病毒群体的分子特征，包括基因型和表型抗性，趋化因子受体利用和克隆分析，以证明早期建立区隔感染。最终目的是利用上述技术，通过对因独立于本建议的原因而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中枢神经系统原发性HIV病程的影响。HIV原发感染的确定是建立中枢神经系统感染和损伤的关键时期，揭示中枢神经系统治疗的早期效果，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更好地理解和治疗艾滋病毒的中枢神经系统并发症。参加正式的临床研究高级培训项目将培养成熟和负责任的研究。神经病学的临床服务将包括对艾滋病患者以及其他传染病患者的护理。最后，博士的指导。Price， Meyerhoff和Hecht以及UCSF神经内科的支持将使申请人成为学术界不可或缺的一员。

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.