HIV-1 Tat genetic variation impacts NeuroAIDS

HIV-1 Tat 遗传变异影响 NeuroAIDS

• 批准号: 10553612
• 负责人: Sandhya Kortagere
• 金额: $ 60.31万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553612
• 关键词: APOCEC3G gene; Acquired Immunodeficiency Syndrome; Affect; Amino Acid Sequence; Amino Acids; Architecture; Astrocytes; Behavior; Behavioral; Binding; Biological Assay; Blood Vessels; Blood specimen; Brain; Cells; Central Nervous System; Cohort Studies; Consensus; Data; Defective Viruses; Development; Dose; Etiology; Experimental Designs; Frequencies; Funding; Generations; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genome; HIV; HIV-1; HIV-associated neurocognitive disorder; Histology; Impaired cognition; Impairment; In Vitro; Individual; Infection; Integration Host Factors; Lead; Macrophage; Mediating; Medicine; Microglia; Midbrain structure; Modeling; Molecular Target; Mutation; N-Methyl-D-Aspartate Receptors; National NeuroAids Tissue Consortium; Nervous System Physiology; Network-based; Neurocognitive; Neurocognitive Deficit; Neuronal Dysfunction; Neurons; Neuropathogenesis; Neuropsychology; Pathogenesis; Pathway interactions; Patients; Positioning Attribute; Prefrontal Cortex; Production; Proteins; Proviruses; RNA-Directed DNA Polymerase; Rattus; Receptor Inhibition; Recovery; Research; Rodent Model; Scoring Method; Surface; Surface Plasmon Resonance; T-Lymphocyte; Testing; Tissues; Trans-Activators; Transactivation; Transcription Coactivator; Transcriptional Activation; Transfection; Variant; Viral; Viral Load result; Virus Integration; antiretroviral therapy; behavioral outcome; brain tissue; cell type; convolutional neural network; diagnostic assay; experimental study; extracellular; fetal; genetic variant; in silico; in vivo; in vivo Model; molecular modeling; monocyte; neuroAIDS; neurotoxicity; novel; novel therapeutics; peripheral blood; pharmacologic; prevent; protein protein interaction; receptor; response; tat Genes

Project Abstract/Summary The viral load can be controlled in the periphery of HIV-1-infected patients through consistent use of antiretroviral therapy (ART). Despite this, over 50% of HIV-infected patients are predicted to suffer from HIV-associated neurocognitive impairment (NCI). Although the pathogenesis of NCI is incompletely understood, HIV-1 transactivator of transcription (Tat) has been shown to be capable of being secreted from infected cells, and once extracellular within the central nervous system (CNS) it will induce neuronal dysregulation. Early in the infection, HIV-1 has been shown to establish a reservoir in the brain, either by entering as infected perivascular macrophages or infecting resident microglia, prior to the patient receiving ART. ART does not affect the production of Tat, which is continually made in these cells, leading to quantifiable levels of Tat in the absence of detectable viral load. Tat sequence composition varies within and between individuals due to HIV-1’s error-prone reverse transcriptase and host factors such as APOBEC3G. In the previous 5 years, we have shown that this variation is associated with NCI, as shown by our studies comparing the HIV-1 Tat protein sequence composition from impaired and non-impaired patients within the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. Residues associated with NCI included 59P, 74H, and 12K, while 36V, 40T, 63E, and 23T were associated with non-impairment. Effects of Tat variation can be further exemplified by Tat’s interaction with the NMDA receptor (NMDAR). This interaction can be weakened when Tat undergoes a C31S mutation, as shown in HIV-1 subtype C infections. Our preliminary data has shown that Tat genetic variants within the CARES Cohort have different predicted interaction profiles with GRIN2A, a subunit of NMDAR. Although the Tat-NMDAR interaction has been shown to be an established driver of HAND, it may not be the only factor involved in NCI in neuroHIV. Given this, we hypothesize that HIV-1 Tat genetic variation may cause differential secretion of Tat and/or affect Tat’s binding to molecular targets leading to neuronal dysfunction that underlies NCI in neuroHIV. To investigate this, we propose three Aims. Aim 1 will determine if amino acid variations in Tat associated with NCI via peripheral blood sampling correlates to that found in the CNS and/or intact provirus. Aim 2 will explore the impact of HIV-1 Tat genetic variation on protein-protein interactions that contribute to HAND pathogenesis. Aim 3 will assess the contribution of HIV-1 Tat variants to NCI using an in vivo model of Tat-induced neuropathogenesis. Overall, these studies will contribute to defining the mechanism of how HIV-1 Tat polymorphisms alter interactions with neurons and ultimately affect CNS function. Successful completion of the proposed project will result in a better understanding of the etiology of HAND, potential development of diagnostic assay for HAND, and identification of novel Tat-mediated targets for treating NCI.

项目摘要/摘要 通过持续使用抗逆转录病毒药物，可以控制HIV-1感染患者周围的病毒载量 治疗（ART）。尽管如此，预计超过50%的艾滋病毒感染者将患有艾滋病毒相关疾病。 神经认知障碍（NCI）。虽然NCI的发病机制还不完全清楚，但HIV-1 转录的反式激活因子（达特）已经显示能够从感染的细胞分泌，并且 一旦在中枢神经系统（CNS）内的细胞外，它将诱导神经元失调。早在 感染后，HIV-1已被证明可以在大脑中建立一个储存库，或者通过感染的血管周围进入大脑， 在患者接受ART之前，ART不影响巨噬细胞或感染驻留的小胶质细胞。 达特的产生，其在这些细胞中持续产生，导致在不存在Tat的情况下达特的可定量水平。 可检测的病毒载量达特序列组成在个体内和个体之间是不同的，这是由于HIV-1的易错性。 逆转录酶和宿主因子如APOBEC 3G。在过去的五年里，我们已经证明， 我们的研究比较了HIV-1达特蛋白序列组成，结果表明，变异与NCI相关 来自Drexel Medicine CNS AIDS研究和根除研究中的受损和非受损患者 （CARES）队列。与NCI相关的残基包括59 P、74 H和12 K，而36 V、40 T、63 E和23 T， 与非损伤相关。达特变异的影响可以通过达特与 NMDA受体（NMDAR）。当达特经历C31 S突变时，这种相互作用可以减弱，如 在HIV-1亚型C感染中显示。我们的初步数据表明，CARES中的达特基因变异 队列具有不同的预测与GRIN 2A，NMDAR的亚基的相互作用的配置文件。虽然Tat-NMDAR 虽然已经证明交互作用是HAND的既定驱动因素，但它可能不是NCI中涉及的唯一因素， 神经HIV。鉴于此，我们假设HIV-1达特基因变异可能导致达特的差异分泌 和/或影响达特与分子靶的结合，导致神经元功能障碍，这是神经HIV中NCI的基础。 为了研究这个问题，我们提出了三个目标。目的1将确定达特中的氨基酸变异是否与以下相关： 通过外周血采样的NCI与CNS和/或完整前病毒中发现的NCI相关。Aim 2将探索 HIV-1达特基因变异对HAND发病机制中蛋白质-蛋白质相互作用的影响。 目的3将使用Tat诱导的NCI的体内模型评估HIV-1达特变体对NCI的贡献。 神经发病机制总体而言，这些研究将有助于确定HIV-1达特的机制 多态性改变与神经元的相互作用并最终影响CNS功能。成功完成 拟议的项目将导致更好地了解病因的手，潜在的发展诊断 用于HAND的测定，以及用于治疗NCI的新型Tat介导的靶标的鉴定。