Correlates of Monocyte-Associated Virus in HIV Neurocognitive Impairment

单核细胞相关病毒与 HIV 神经认知损伤的相关性

• 批准号: 8102804
• 负责人: WILLIAM Albert BLATTNER
• 金额: $ 66.16万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102804
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Address; Adverse effects; Affect; African; Anti-Retroviral Agents; Applications Grants; Attention; Binding Sites; Blood; Blood - brain barrier anatomy; Blood Cells; Brain; CD14 gene; California; Cells; Cerebrospinal Fluid; Classification; Clinical; Comorbidity; Coupled; Cross-Sectional Studies; DNA; Data; Development; Drug resistance; Enrollment; Frequencies; Future; Genotype; HIV; HIV Infections; HIV encephalitis; HIV-1; Human Virology; Impairment; Individual; Inflammatory; Institutes; Laboratories; Link; Manuscripts; Maryland; Measurement; Measures; Molecular Virology; Mononuclear; Mus; Natural History; Neurocognitive; Neuropsychological Tests; Nigeria; Outcome; Pathogenesis; Patients; Pattern; Penetrance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Plasma Cells; Preparation; Process; Proviruses; Public Health; RNA; Recruitment Activity; Regulator Genes; Reporting; Research; Research Personnel; Role; Sahara; Satellite Viruses; Scientist; Severities; Techniques; Testing; Tropism; Universities; Viral; Viral Drug Resistance; Viral Load result; Virus; brain tissue; cohort; env Genes; follow-up; improved; international center; macrophage; mild neurocognitive impairment; monocyte; neurobehavioral; pol genes; programs; prospective; public health relevance; repository; residence; response; success; trafficking; treatment adherence; treatment response; viral RNA

DESCRIPTION (provided by applicant): Improved and more sensitive techniques for detecting the range of HIV-induced neurocognitive impairment (NCI) [asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) or HIV-associated dementia (HAD)] document NCI as a major co-morbidity of HIV-1 (HIV) infection. Building on the confluence of new information showing that CD14-positive Monocyte-associated HIV DNA Viral Load (CD14MADVL) correlates with NCI, coupled to unpublished data from co-investigator S. Gartner documenting a highly distinct virus in CD14 positive monocyte, the current proposal targets in depth pathogenesis research of the virus in this compartment drawing from a unique prospective cohort of treatment naive patients recruited from a large Nigerian PEPFAR program. The conceptual framework for this project draws from the well established fact that HIV enters the brain primarily via the trafficking of infected blood monocytes and virus in this compartment provides a window for understanding the pathogenesis of NCI without direct access to brain tissue. Our preliminary studies document capacity to enroll and detect large numbers of treatment naive patients with NCI, maintain them in prospective follow up and perform in depth laboratory analysis of the virus from monocytes, CD-14 negative mononuclear cells, plasma and CSF. The central hypothesis of this grant application is that the previously reported correlation between severity of NCI and CD14MADVL is linked to a distinctive pattern of viral quasi-species in this compartment (unpublished preliminary data) and that detailed analysis of viral motifs among the quasi-species from this compartment compared to non-monocyte HIV DNA and plasma viral RNA offer promise for identifying signature patterns that will inform NCI pathogenesis. This hypothesis will be addressed in two aims: Aim 1 - Classification of NCI and correlation with CD14MADVL in cross sectional study and longitudinally, and Aim 2 - Detailed study of the virus engaging targeted quasi-species analysis to characterize distinguishing motifs associated with NCI, and to study the relationship to viral subtype and the relationship of viral drug resistance in different compartments to NCI. The research team is comprised of internationally recognized HIV, neuro-AIDS and molecular virology experts from the University of Maryland, leading neuro-AIDS scientists from the University of California San Diego HIV Neurobehavioral Research Center (UCSD/HNRC), and local research investigators from the Institute of Human Virology-Nigeria (IHV-N) and affiliates in Nigeria. Additionally an extensive repository of viable peripheral blood cells, DNA and plasma will be collected for future studies. PUBLIC HEALTH RELEVANCE: The public health implications are that a high frequency of impairment in the ability of people to think clearly due to HIV infection can have adverse effects on treatment success. The current project will provide information on how frequently this impairment occurs and to understand how the virus causes this impairment.

描述（由申请人提供）：用于检测 HIV 引起的神经认知障碍 (NCI) 范围的改进且更灵敏的技术 [无症状神经认知障碍 (ANI)、轻度神经认知障碍 (MND) 或 HIV 相关痴呆 (HAD)] 文件 NCI作为 HIV-1 (HIV) 感染的主要并发症。基于显示 CD14 阳性单核细胞相关 HIV DNA 病毒载量 (CD14MADVL) 与 NCI 相关的新信息的融合，再加上共同研究者 S. Gartner 未发表的数据，记录了 CD14 阳性单核细胞中存在高度独特的病毒，当前的提案该项目的目标是对该隔室中的病毒进行深入的发病机制研究，该研究的对象是从尼日利亚大型总统防治艾滋病紧急救援计划（PEPFAR）计划中招募的未接受过治疗的独特前瞻性患者队列。该项目的概念框架借鉴了一个公认的事实，即艾滋病毒主要通过受感染的血液单核细胞的运输进入大脑，而该区室中的病毒为了解 NCI 的发病机制提供了一个窗口，而无需直接进入脑组织。我们的初步研究记录了招募和检测大量未经治疗的 NCI 患者的能力，对他们进行前瞻性随访，并对单核细胞、CD-14 阴性单核细胞、血浆和脑脊液中的病毒进行深入的实验室分析。该拨款申请的中心假设是，先前报道的 NCI 严重程度和 CD14MADVL 之间的相关性与该区室中病毒准种的独特模式有关（未发表的初步数据），并且对准种中病毒基序的详细分析与非单核细胞 HIV DNA 和血浆病毒 RNA 相比，该区室的 DNA 为识别特征模式提供了希望，从而为 NCI 发病机制提供信息。这一假设将通过两个目标来实现：目标 1 - 在横断面研究和纵向研究中对 NCI 进行分类以及与 CD14MADVL 的相关性；目标 2 - 通过有针对性的准种分析对病毒进行详细研究，以表征与 NCI 相关的区别基序；以及研究与病毒亚型的关系以及不同区室的病毒耐药性与NCI的关系。该研究团队由来自马里兰大学的国际公认的艾滋病毒、神经艾滋病和分子病毒学专家、来自加州大学圣地亚哥分校艾滋病毒神经行为研究中心（UCSD/HNRC）的顶尖神经艾滋病科学家以及来自美国的当地研究人员组成。尼日利亚人类病毒学研究所 (IHV-N) 及其在尼日利亚的附属机构。此外，还将收集大量的活外周血细胞、DNA 和血浆，用于未来的研究。 公共卫生相关性：对公共卫生的影响是，由于艾滋病毒感染，人们的清晰思考能力频繁受损，可能会对治疗的成功产生不利影响。当前的项目将提供有关这种损害发生频率的信息，并了解病毒如何导致这种损害。