Defining CNS HIV Infection in Treated Patients: Foundation for Eradication

定义接受治疗的患者中枢神经系统 HIV 感染：根除的基础

• 批准号: 8262531
• 负责人: RICHARD W. PRICE
• 金额: $ 22.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-11 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262531
• 关键词: AIDS Dementia Complex; Biological Assay; Biological Markers; Central Nervous System Diseases; Central Nervous System Infections; Cerebrospinal Fluid; Characteristics; Chronic; Clinical; Disease; Drug Combinations; Foundations; Frequencies; Future; Genetic; HIV; HIV Infections; Immune; Impairment; Incidence; Individual; Infection; Injury; Measurable; Measurement; Measures; Methods; Natural History; Nervous system structure; Neuraxis; Neurocognitive; Neurologic; Neuropsychological Tests; Patients; Penetration; Performance; Pharmaceutical Preparations; Phylogenetic Analysis; Plasma; Population; RNA; Regimen; Residual state; Sampling; Source; Techniques; Testing; Viral; Viral Load result; Viremia; Virus; antiretroviral therapy; follow-up; functional disability; genome sequencing; immune activation; nerve injury; novel; relating to nervous system; viral RNA; viral detection

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.

描述（由申请人提供）： 拟议的研究集中于中枢神经系统（CNS）HIV感染及其在治疗血浆病毒抑制患者中的后果。在两个目标中的第一个中，我们将使用病毒RNA的超敏感单复制测定（SCA）来定义一组“良好治疗”患者的脑脊液（CSF）感染的存在和大小，并检查'免疫激活和神经损伤以及神经心理学测试表现的CSF生物标志物的残留'CSF感染。我们还将评估残留的CSF感染是否与药物渗透特征相关。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生和残留CSF HIV的起源。尽管抗逆转录病毒疗法对严重的中枢神经系统HIV疾病产生了显着影响，但治疗患者的持续性中枢神经系统感染仍然可能是慢性，CNS免疫激活和损伤的驱动因素，以及作为一个病毒储层，需要由病毒剥落策略来瞄准。拟议的研究将提供有关“经过良好治疗”患者中CNS HIV感染的频率，特征和后果的独特而基本的信息，并为根除针对这种感染的策略提供了基础。 公共卫生相关性： 尽管抗逆转录病毒疗法有效地减少了HIV感染的更严重的神经系统并发症，但不幸的是，HIV中枢神经系统（CNS）感染在治疗患者中仍然很重要。患者继续显示出温和的证据，但仍然很重要，神经认知障碍以及免疫学异常以及脑脊液中感染的突破（CSF），表明神经系统中继续感染，并且随着治疗方法开始扩展到病毒策略的策略。根除或治愈，该CNS感染可能是一个限制因素。在将非常敏感的病毒检测方法应用于CSF之后，以进一步定义“经过良好处理”患者中HIV感染的存在后，这些研究的结果将提供有关HIV持续性及其对CNS的持久性的新颖而重要的信息治疗以及评估未来根除策略的中枢神经系统影响的方法。