Correlates of Monocyte-Associated Virus in HIV Neurocognitive Impairment

描述(由申请人提供)：用于检测艾滋病毒引起的神经认知障碍(NCI)[无症状神经认知障碍(ANI)、轻度神经认知障碍(MND)或艾滋病毒相关痴呆(HAD)]范围的改进和更灵敏的技术证明NCI是HIV-1感染的主要共同发病。基于显示CD14阳性单核细胞相关HIV DNA病毒载量(CD14MADVL)与NCI相关的新信息的汇合，再加上合作者S.Gartner记录了CD14阳性单核细胞中一种高度独特的病毒的未发表数据，目前的提案针对这一隔室中病毒的深入发病机制研究，该病毒来自从尼日利亚PEPFAR大型计划招募的独特的预期治疗初治患者队列。这一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感染的血液单核细胞的运输进入大脑，而病毒在这个隔间为了解NCI的发病机制提供了一个窗口，而不是直接接触脑组织。我们的初步研究证明，我们有能力招募和检测大量未接受治疗的NCI患者，保持他们的前瞻性随访，并对来自单核细胞、CD-14阴性单核细胞、血浆和脑脊液的病毒进行深入的实验室分析。这项赠款申请的中心假设是，先前报道的NCI和CD14MADVL严重程度之间的相关性与这一区域中病毒准物种的独特模式(未发表的初步数据)有关，并且对该区域中准物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，为识别将告知NCI发病机制的特征模式提供了希望。这一假设将在两个目标下进行：目标1-NCI的分类及其与CD14MADVL在横断面和纵向研究中的相关性，以及目标2-对该病毒进行有针对性的准物种分析，以表征与NCI相关的区分基序，并研究与病毒亚型的关系以及不同分区对NCI的病毒耐药性关系。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、加州大学圣地亚哥分校艾滋病毒神经行为研究中心(UCSD/HNRC)的领先神经艾滋病科学家以及尼日利亚人类病毒学研究所(IHV-N)及其附属机构的当地研究人员组成。此外，还将收集大量可存活的外周血细胞、DNA和血浆，以供未来研究。 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，可能会对治疗成功产生不利影响。目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。

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showing that CD14-positive Monocyte-associated HIV DNA Viral Load (CD14MADVL) correlates with NCI, coupled to unpublished data from co-investigator S. Gartner documenting a highly distinct virus in CD14 positive monocyte, the current proposal targets in depth pathogenesis research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.