SOURCES AND NEUROCOGNITIVE CORRELATES ON CSF HIV RNA

描述（改编自申请人的摘要）： 中枢神经系统（CNS）HIV感染的后果是 由于神经认知障碍导致的残疾，生活质量下降，以及 生存率下降。发病机制的研究进展， 这些疾病的治疗是至关重要的。本研究提案 概述了三个综合的实验室和临床研究， 检查CSF RNA的来源，CNS作为储存库的潜在作用， 以及监测脑脊液（CSF）病毒载量如何指导 CNS的抗逆转录病毒治疗。第一项研究是一种抗逆转录病毒药物 旨在最大限度降低患者CSF病毒载量的治疗试验 与HIV相关的神经认知障碍（N = 45）。这次审判将检验 假设神经认知功能的改善可以通过 通过降低脑脊液病毒载量在第二项研究中， 具有和不具有晚期免疫抑制的未治疗个体（n=42）， 将被随机分配到CNS穿透性和非穿透性 抗逆转录病毒联合治疗，以及CSF和 将连续测定血浆HIV RNA病毒载量。这项研究将测试 假设在晚期疾病中，生产性脑感染是 CSF中HIV的主要来源，合理的治疗需要 CNS穿透性抗逆转录病毒药物。这两项研究将连续记录 血浆和CSF抗逆转录病毒药物浓度。第三项研究， 对10名患者的生前和死后样本进行分析， 病毒在各种系统和中枢神经系统区室中的系统发育相关性 为了证实这一假设，即随着艾滋病的发展， CSF中的变异类似于脑中的变异。类似方法，适用于CSF 从治疗试验参与者中获得，将评估 CNS中HIV的耐药突变。这项研究将 为艾滋病毒感染的合理诊断和治疗奠定基础 与艾滋病毒神经行为研究中心有着独特的合作关系。 招募、神经医学诊断、神经心理学中心 评估和获取死前和死后样本。

DESCRIPTION (Adapted from the Applicant's Abstract): The social and medical consequences of HIV infection of the central nervous system (CNS) are disability due to neurocognitive disorders, lowered quality of life, and decreased survival. Advances in the understanding of the pathogenesis and treatment of these disorders are vitally important. This research proposal outlines three integrated laboratory and clinical investigations that will examine the sources of CSF RNA, the potential role of the CNS as reservoir for HIV, and how monitoring cerebrospinal fluid (CSF) viral load may guide antiretroviral therapy for the CNS. The first study is an antiretroviral treatment trial designed to maximally diminish CSF viral load in patients with HIV-associated neurocognitive disorders (N = 45). This trial will test the hypothesis that improvement in neurocognitive function may be achieved through a reduction in CSF viral load. In a second study, previously untreated individuals with and without advanced immunosuppression (n=42), will be randomly assigned to CNS penetrating and nonpentrating antiretroviral combination therapies, and the dynamic change of CSF and plasma HIV RNA viral load will be determined serially. This study will test the hypothesis that in late stage disease, productive brain infection is the primary source of HIV in CSF, and that rational therapy requires CNS-penetrating antiretroviral drugs. Both studies will serially document plasma and CSF antiretroviral drug concentrations. A third study, drawing on antemortem and postmortem samples from 10 patients, will assess the phylogenetic relatedness of virus in various systemic and CNS compartments to confirm the hypothesis that as AIDS develops, the predominant HIV genetic variant in CSF resembles that in brain. Similar methodology, applied to CSF obtained from treatment trial participants, will assess the evolution of drug resistant mutations of HIV in the CNS. This research, which will provide groundwork for the rational diagnosis and treatment of HIV infection of the CNS, has a unique collaboration with the HIV Neurobehavioral Research Center for recruitment, neuromedical diagnosis, neuropsychological assessment, and acquisition of antemortem and postmortem samples.