Defining CNS HIV Infection in Treated Patients: Foundation for Eradication

描述(由申请人提供)： 拟议的研究集中在中枢神经系统(CNS)HIV感染及其对接受血浆病毒抑制治疗的患者的后果。在两个目标中的第一个，我们将使用病毒RNA的超灵敏单拷贝分析(SCA)来确定一组经过良好治疗的患者脑脊液(CSF)感染的存在和程度，并检测脑脊液感染对免疫激活和神经损伤的脑脊液生物标记物以及神经心理测试成绩的影响。我们还将评估残留的脑脊液感染是否与联合药物的渗透特性有关。在第二个目标中，我们将使用敏感的单基因组测序(SGS)方法和系统发育关系来分析治疗患者中病毒逃逸和残留脑脊液HIV的来源。虽然抗逆转录病毒治疗对严重的中枢神经系统艾滋病毒疾病产生了显著影响，但接受治疗的患者中持续的中枢神经系统感染仍然具有潜在的重要意义，因为它是慢性、持续的中枢神经系统免疫激活和损伤的驱动因素，也是病毒根除战略需要瞄准的病毒库。拟议的研究将提供有关“经过良好治疗”的患者中持续感染CNS艾滋病毒的频率、特征和后果的独特和重要的信息，并为针对这种感染的根除战略提供基础。 公共卫生相关性： 虽然抗逆转录病毒治疗有效地减少了艾滋病毒感染引起的更严重的神经系统并发症，但不幸的是，艾滋病毒感染中枢神经系统(CNS)在接受治疗的患者中仍然很重要。患者继续表现出轻微但仍然重要的神经认知损害的证据，以及免疫异常和脑脊液(CSF)感染的突破，这表明神经系统持续感染，随着治疗方法开始扩展到病毒根除或治愈的策略，这种中枢神经系统感染可能被证明是一个限制因素。在将非常敏感的病毒检测方法应用于脑脊液以进一步确定“治疗良好”的患者中是否存在艾滋病毒感染之后，这些研究的结果将提供关于艾滋病毒的持久性及其在治疗后对中枢神经系统的影响的新的和重要的信息，以及评估未来根除策略的中枢神经系统影响的方法。

DESCRIPTION (provided by applicant): The proposed studies focus on central nervous system (CNS) HIV infection and its consequences in treated patients with plasma viral suppression. In the first of two aims, we will use the ultrasensitive single copy assay (SCA) of viral RNA to define the presence and magnitude of cerebrospinal fluid (CSF) infection in a group of 'well-treated' patients and examine the impact of 'residual' CSF infection on CSF biomarkers of immunoactivation and neural injury and on neuropsychological test performance. We will also assess whether residual CSF infection relates to combination drug penetration characteristics. In the second aim, we will use sensitive single genome sequencing (SGS) methods and phylogenetic relationships to analyze the origins of viral escape and residual CSF HIV in treated patients. While antiretroviral therapy has had a remarkable impact on severe CNS HIV disease, persistent CNS infection in treated patients remains potentially important as the driver of chronic, continued CNS immunoactivation and injury, and as a viral reservoir that needs to be targeted by viral eradication strategies. The proposed studies will provide unique and essential information regarding the frequency, character and consequences of continued CNS HIV infection in 'well-treated' patients and also provide a foundation for eradication strategies targeting this infection. PUBLIC HEALTH RELEVANCE: While antiretroviral therapy has effectively reduced the more severe neurological complications of HIV infection, central nervous system (CNS) infection by HIV unfortunately remains important in treated patients. Patients continue to show evidence of milder, but still important, neurocognitive impairment along with immunological abnormalities and breakthrough of infection in the cerebrospinal fluid (CSF), suggesting continued infection in the nervous system, and, as treatment approaches begin to extend to strategies for viral eradication or cure, this CNS infection may prove a limiting factor. After applying very sensitive viral detection methods to CSF in order to further define the presence of HIV infection in 'well-treated' patients, the results of these studies will provide novel and important information regarding the persistence of HIV and its effects on the CNS despite treatment, as well as methods for evaluating the CNS effects of future eradication strategies.