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 病毒载量可以通过持续使用抗肠病毒来控制HIV-1感染患者的外围 治疗（ART），尽管有超过50％的HIV感染患者 神经认知障碍（NCI）。 转录剂（TAT）已被证明能够从感染细胞中分泌 一旦中枢神经系统（CNS）的细胞外诱导神经元失调 感染已被证明是在大脑中建立一个水库 在患者接受ART之前，ALT不会影响巨噬细胞或感染居民小胶质细胞。 在这些细胞中持续制造的TAT的产生，导致在没有的情况下可量化的TAT水平 可检测的病毒负载。 逆转录酶和主机因素，例如apobec3g。 变体与NCI相关，如我们的研究所示，组成HIV-1 TAT蛋白序列组成 来自Delesel Medicine中的受损和未受损的患者CNS AIDS研究和根除研究 （照顾）与NCI相关的居民包括59p，74h和12k，而36V，40T，63E和23T 与不损害相关。 NMDA受体（NMDAR）。 在HIV-1亚型C感染中显示。 队列与Grin2a（NMDAR的亚基）具有不同的预测相互作用曲线。 互动已被证明已建立了手的驱动程序 鉴于这一点，我们假设HIV-1 TAT遗传变异可能会导致TAT的差异 和/或影响TAT的结合耐受靶标，导致神经元功能性tasfunction tasfunctis nci在神经hiv中。 为了调查这一点，我们提出了三个目标。 NCI通过外周血采样与CNS和/或Intact Provirus相关。 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 神经发病的总体而言，这些研究有助于防御HIV-1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。 支撑项目将更好地了解手的病因，潜在的诊断发展 手工分析，并鉴定了新型TAT介导的NCI介导的靶标。