Neuropathogenesis of clade C HIV in South Africa

南非 C 型 HIV 的神经发病机制

• 批准号: 7757756
• 负责人: Robert H Paul
• 金额: $ 72.79万
• 依托单位: UNIVERSITY OF MISSOURI-ST. LOUIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7757756
• 关键词: Address; Affect; Affinity; African; Biological; Biological Markers; Brain; Brain region; Characteristics; Chemokine (C-C Motif) Receptor 5; Clinic; Cognition; Cognitive; DNA; Data; Defect; Diffusion; Diffusion Magnetic Resonance Imaging; Education; Ethiopia; Exhibits; Fiber; Goals; HIV; HIV Seropositivity; Health; Impaired cognition; Impairment; India; Individual; Inflammatory; International; Laboratories; Laboratory Markers; Language; Learning; Length; Magnetic Resonance Imaging; Methods; Metric; Missouri; Modeling; Motor; Neuropathogenesis; Neuropsychology; North America; Outcome; Patients; Performance; Plasma; Population; Process; Psychiatry; Recruitment Activity; Relative (related person); Reporting; Research; Research Personnel; Risk; South Africa; Speed; System; Testing; Universities; Variant; Viral; Viral Proteins; Virus; Work; brain behavior; cognitive function; cohort; cytokine; executive function; genetic strain; indexing; insight; member; monocyte; neurobehavioral; neuroimaging; neuropathology; neuropsychological; neurovirulence; novel; novel marker; public health relevance; statistics; tat Protein; trafficking; virology; white matter

DESCRIPTION (provided by applicant): The proposed study will capitalize on existing relationships between the University of Missouri, St. Louis, and the University of Cape Town, South Africa to characterize the neurobehavioral signatures of HIV in South African individuals infected with clade C virus. Clade C represents the most common form of HIV in the world and it remains a dominant strain in South Africa. Early studies suggested that individuals infected with clade C HIV may be less likely to develop cognitive impairments due to a natural variation in the dicysteine motif of the Tat protein (C31S) evident in clade C virus. In support of this hypothesis a recent study of individuals infected with clade C virus in Ethiopia exhibited minimal cognitive impairment. However, other biological studies suggest that clade C may infer neurovirulence and we have demonstrated that patients with clade C virus in India exhibit cognitive impairment relative to seronegative controls. Recently we have collected data from a small group of individuals infected with clade C in South Africa, and we also have obtained neuroimaging on HIV patients in South Africa. These preliminary studies suggest that cognition is likely negatively affected in clade C patients residing in South Africa. However, it is unknown whether the cognitive impairments identified in clade C are present in the context of the Tat protein defect, or whether they relate to other known virologic correlates of cognitive function such as proviral DNA level. Further, no study has addressed the neuroimaging signatures of clade C HIV. In the present study we will examine 200 treatment-naive, HIV-positive individuals with clade C HIV and 50 seronegative healthy controls matched on demographic characteristics and all recruited from South Africa. Laboratory, cognitive, and neuroimaging data will be obtained from the patients and controls. Neuroimaging will consist of diffusion tensor imaging (DTI) to derive novel metrics of quantified tractography developed by members of our team (Laidlaw) as well as traditional volumetric indices that are known neuriomaging signatures of impairment in clade B HIV. This will be the first transdisciplinary study of clade C neuropathogenesis and the results will significantly advance our understanding of viral clade diversity and cognitive outcomes associated with HIV. PUBLIC HEALTH RELEVANCE: The purpose of this study is to determine the impact of clade C HIV on cognitive function among individuals in South Africa. We aim to demonstrate that cognitive impairment is present among individuals infected with clade C despite the presence a Tat protein defect. We also aim to demonstrate that these impairments correlate with proviral DNA levels and markers of novel neuroimaging signatures.

描述（由申请人提供）：拟议的研究将利用密苏里大学圣路易斯分校和南非开普敦大学之间的现有关系来描述感染 C 分支病毒的南非个体中 HIV 的神经行为特征。 C 分支代表了世界上最常见的艾滋病毒形式，并且仍然是南非的主要毒株。早期研究表明，由于 C 分支病毒中明显的 Tat 蛋白 (C31S) 双半胱氨酸基序的自然变异，感染 C 分支 HIV 的个体可能不太可能出现认知障碍。为了支持这一假设，最近一项针对埃塞俄比亚 C 分支病毒感染者的研究显示出轻微的认知障碍。然而，其他生物学研究表明，C 分支可能推断出神经毒力，并且我们已经证明，印度 C 分支病毒患者相对于血清阴性对照表现出认知障碍。最近，我们收集了南非一小群 C 分支感染者的数据，我们还获得了南非 HIV 患者的神经影像学数据。这些初步研究表明，居住在南非的 C 分支患者的认知可能受到负面影响。然而，尚不清楚 C 分支中发现的认知障碍是否存在于 Tat 蛋白缺陷的背景下，或者它们是否与认知功能的其他已知病毒学相关因素（例如前病毒 DNA 水平）有关。此外，尚无研究探讨 C 型 HIV 的神经影像学特征。在本研究中，我们将检查 200 名未接受过治疗、感染 C 型 HIV 的 HIV 阳性个体和 50 名与人口特征相匹配的血清学阴性健康对照，并且全部从南非招募。将从患者和对照组获得实验室、认知和神经影像数据。神经影像学将包括弥散张量成像 (DTI)，以得出由我们团队成员 (Laidlaw) 开发的量化纤维束成像的新指标，以及已知的 B 型 HIV 损伤神经影像学特征的传统体积指数。这将是第一个针对 C 分支神经发病机制的跨学科研究，其结果将显着增进我们对病毒分支多样性和与 HIV 相关的认知结果的理解。公共卫生相关性：本研究的目的是确定 C 分支 HIV 对南非个体认知功能的影响。我们的目的是证明，尽管存在 Tat 蛋白缺陷，但感染 C 进化枝的个体仍存在认知障碍。我们还旨在证明这些损伤与前病毒 DNA 水平和新型神经影像特征标记相关。