HIV-1 Tat genetic variation impacts NeuroAIDS

HIV-1 Tat 遗传变异影响 NeuroAIDS

• 批准号: 10377319
• 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/10377319
• 关键词: APOCEC3G gene; Acquired Immunodeficiency Syndrome; Affect; Amino Acid Sequence; Amino Acids; Architecture; Astrocytes; Behavior; Behavioral; Binding; Biological Assay; Blood specimen; Brain; Cells; Cohort Studies; Consensus; Custom; Data; Defective Viruses; Development; Dose; Etiology; 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; Mediating; Medicine; Microglia; Midbrain structure; Modeling; Molecular Target; Mutation; N-Methyl-D-Aspartate Receptors; National NeuroAids Tissue Consortium; Nervous System Physiology; Network-based; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neuronal Dysfunction; Neurons; Neuropathogenesis; Neuropsychology; Pathogenesis; Pathway interactions; Patients; Pharmacology; 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; Transfection; Variant; Viral; Viral Load result; Virus; antiretroviral therapy; behavioral outcome; brain tissue; cell type; convolutional neural network; design; diagnostic assay; experimental study; extracellular; fetal; genetic variant; in silico; in vivo; in vivo Model; macrophage; molecular modeling; monocyte; neuroAIDS; neurotoxicity; novel; novel therapeutics; peripheral blood; 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 可以通过持续使用抗逆转录病毒来控制HIV-1感染患者的外围病毒载荷 治疗（艺术）。尽管如此，预计超过50％的HIV感染患者患有HIV相关的患者 神经认知障碍（NCI）。尽管不完全了解NCI的发病机理，但HIV-1 转录剂（TAT）已显示能够从感染细胞中分泌，并且 一旦中枢神经系统（CNS）内细胞外，它将诱导神经元失调。在早期 感染，HIV-1已显示出在大脑中建立储层，要么通过感染周围的血管内 巨噬细胞或感染的居民小胶质细胞，在患者接受艺术之前。艺术不影响 在这些细胞中不断制造的TAT的产生，导致TAT的可量化水平 可检测的病毒负荷。 TAT序列组成因HIV-1易于错误而导致的个体内部和在个人之间有所不同 逆转录酶和宿主因素（例如Apobec3g）。在过去的5年中，我们已经证明了这一点 变异与NCI相关，如我们的研究所示，比较了HIV-1 TAT蛋白序列组成 从Drexel Medicine CNS AIDS研究和根除研究中的受损和未受损的患者 （在乎）队列。与NCI相关的残留物包括59p，74h和12k，而36V，40T，63E和23T 与非损害有关。 TAT与Tat的相互作用可以进一步说明TAT变化的影响 NMDA受体（NMDAR）。当Tat经历C31S突变时，这种相互作用可以削弱 在HIV-1亚型C感染中显示。我们的初步数据表明，CARES内的TAT遗传变异 队列与Grin2a（NMDAR的亚基）具有不同的预测相互作用曲线。虽然是tat-nmdar 互动已被证明是一位已建立的手驱动力，它可能不是NCI涉及的唯一因素 Neurohiv。鉴于此，我们假设HIV-1 TAT遗传变异可能导致TAT的分泌差分 和/或影响TAT与分子靶标的结合，导致神经元功能障碍，这是NCI构成神经hohiv的基础。 为了调查这一点，我们提出了三个目标。 AIM 1将确定与TAT的氨基酸变化是否相关 NCI通过外周血采样与中枢神经系统和/或完整病毒中发现的NCI相关。 AIM 2将探索 HIV-1 TAT遗传变异对有助于手动发病机理的蛋白质蛋白相互作用的影响。 AIM 3将使用TAT诱导的体内模型评估HIV-1 TAT变体对NCI的贡献 神经病发生。总体而言，这些研究将有助于定义HIV-1 TAT的机制 多态性改变了与神经元的相互作用，并最终影响中枢神经系统功能。成功完成 拟议的项目将更好地了解手的病因，潜在的诊断发展 手工测定，并鉴定出新的TAT介导的NCI介导的靶标。