Correlates of Monocyte-Associated Virus in HIV Neurocognitive Impairment

描述（由申请方提供）：用于检测HIV诱导的神经认知障碍（NCI）[无症状神经认知障碍（ANI）、轻度神经认知障碍（MND）或HIV相关痴呆（HAD）]范围的改进和更灵敏的技术证明NCI是HIV-1（HIV）感染的主要合并症。基于新信息的汇合，显示CD 14阳性单核细胞相关HIV DNA病毒载量（CD 14 MADVL）与NCI相关，再加上来自合作研究者S. Gartner记录了CD 14阳性单核细胞中的一种高度独特的病毒，目前的提案针对该隔室中病毒的深入发病机制研究，该研究来自一个大型尼日利亚PEPFAR计划招募的独特的前瞻性治疗初治患者队列。该项目的概念框架来自于一个公认的事实，即HIV主要通过感染的血液单核细胞进入大脑，该隔室中的病毒为理解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，使其保持前瞻性随访，并对单核细胞、CD-14阴性单核细胞、血浆和CSF中的病毒进行深入的实验室分析。该基金申请的中心假设是，先前报道的NCI和CD 14 MADVL严重程度之间的相关性与该隔室中病毒准种的独特模式有关（未发表的初步数据），并详细分析了来自该隔室的准种与非种之间的病毒基序，单核细胞HIV DNA和血浆病毒RNA提供了鉴定将告知NCI发病机制的特征模式的希望。这一假设将在两个目标中得到解决：目标1 -NCI的分类以及在横截面研究和纵向研究中与CD 14 MADVL的相关性，以及目标2 -详细研究病毒，进行靶向准种分析以表征与NCI相关的区别性基序，并研究与病毒亚型的关系以及不同隔室中病毒耐药性与NCI的关系。该研究小组由来自马里兰州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艾滋病毒神经行为研究中心（UCSD/HNRC）的领先的神经艾滋病科学家、以及来自尼日利亚人类病毒学研究所（IHV-N）和尼日利亚附属机构的当地研究调查人员组成。此外，将收集大量的活外周血细胞、DNA和血浆储存库用于未来研究。 公共卫生相关性：对公共卫生的影响是，由于艾滋病毒感染，人们清晰思考的能力经常受到损害，这可能对治疗的成功产生不利影响。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showing that CD14-positive Monocyte-associated HIV DNA Viral Load (CD14MADVL) correlates with NCI, coupled to unpublished data from co-investigator S. Gartner documenting a highly distinct virus in CD14 positive monocyte, the current proposal targets in depth pathogenesis research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.