HIV-1 Tat genetic variation impacts NeuroAIDS

HIV-1 Tat 遗传变异影响 NeuroAIDS

• 批准号: 8996738
• 负责人: Michael R Nonnemacher
• 金额: $ 39.13万
• 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 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996738
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Adoption; Affect; Amino Acids; Antiviral Agents; Astrocytes; Automobile Driving; Autopsy; Bioinformatics; Blood - brain barrier anatomy; Brain; CD4 Positive T Lymphocytes; Cell Count; Cell Nucleus; Cells; Cerebrospinal Fluid; Chronic Disease; Clinical; Cohort Studies; Comorbidity; Cytokine Gene; Cytoplasm; Dementia; Development; Disease; Encephalitis; Environment; Exhibits; Extracellular Protein; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Goals; HIV; HIV tat Protein; HIV-1; HIV-associated neurocognitive disorder; Health; Heterogeneity; Highly Active Antiretroviral Therapy; Immunologic Surveillance; Impairment; Individual; Infection; Knowledge; Lead; Length; Life; Link; Lymphocyte; Lymphoid Tissue; Machine Learning; Maps; Messenger RNA; Microglia; Modeling; Molecular Models; Mutation; N-Methyl-D-Aspartate Receptors; Neuraxis; Neurocognitive Deficit; Neurologic; Neurons; Oligodendroglia; Opportunistic Infections; Pathogenesis; Patients; Phylogenetic Analysis; Positioning Attribute; Positive Transcriptional Elongation Factor B; Prevalence; Prevention strategy; Production; Proteins; Reporting; Research; Sequence Analysis; Serum; Severities; Shapes; Structure; Structure-Activity Relationship; Techniques; Therapeutic; Tissues; Toxic effect; Trans-Activators; Transactivation; Vaccines; Variant; Viral; Viral Load result; Virus; base; brain tissue; diagnostic assay; extracellular; genetic regulatory protein; genetic variant; improved; inhibitor/antagonist; innovation; interest; macrophage; molecular modeling; monocyte; nervous system development; nervous system disorder; neuroAIDS; neuron loss; neurotoxic; neurotoxicity; non-demented; novel vaccines; peripheral blood; prediction algorithm; pressure; prevent; protein protein interaction; response; tat Genes; tat Protein; transversion mutation; treatment strategy

 DESCRIPTION (provided by applicant): HIV-1 has demonstrated the ability to cause adverse neurological complications. The introduction of highly active antiretroviral therapy (HAART) has resulted in improved survival, reduced viral loads, increased CD4 T- cell counts, reduced opportunistic infections, and has resulted in a decrease in the most severe form of HIV- associated neurocognitive disorders (HAND), HIV-associated dementia (HAD). However, the overall prevalence of all forms of HAND has increased, potentially because HIV-1-infected individuals are living longer with persistent infection. In addition to activating an antiviral immne response within the CNS, the production of HIV-1 proteins leads to neurotoxicity through direct and indirect mechanisms. Of particular interest is the HIV-1 transactivator protein Tat, which in addition to driving viral transcription also functions as an extracellular neurotoxic protein, activator of astrocytes and microglial cells, and impacts the structure and function of the blood-brain barrier (BBB). Tat is released by infected monocytes, microglial cells, and astrocytes in addition to infected lymphocytes. Tat can be continually produced by HIV-1-infected cells located in the CNS despite the widespread use of HAART, demonstrating that neurologic vulnerability to this protein persists in the HAART era. In addition, mRNA levels for Tat are elevated in brain extracts from individuals with HAD. HIV-1 also displays extensive sequence variation with the quasispecies shaped by many host-specific and comorbidity pressures, while simultaneously maintaining functions that are critical to replication and infectivity as well as pathogenesis. Studies with respect to subtype B Tat genetic variation and HAND have demonstrated (i) Tat sequences from patients in the absence or presence of HAD showed clustering of sequences with respect to neurological impairment as well as tissue of origin, (ii) nonsynonymous versus synonymous mutation rates among brain-derived Tat sequences from patients with HAND were significantly greater than those isolated from patients without neurological disease, and (iii) variation at positions 74 and 100 were correlated to Tat sequences isolated from brain-derived sequences. Importantly, HIV-1 Tat derived from HAD patients has been associated with greater neuronal death. Together, these reports suggest that genetic diversity of HIV-1 Tat likely contributes to the establishment and severity of HAND. Given this, the hypothesis of this application is that patient-derived genetic variants of the HIV- protein Tat are specifically linked with neurologic impairment. To explore this hypothesis, the Specific Aims are to: (1) identify and characterize polymorphisms in HIV-1 Tat from patients with defined degrees of neurocognitive impairment; (2) examine the structural impact of HIV-1 Tat polymorphisms in protein-protein molecular models; and (3) examine the functional impact of the Tat polymorphisms on the BBB and cells of the CNS. These studies will contribute to defining how HIV-1 Tat polymorphisms affect the function of the CNS and the development of HAND and provide information useful in development of diagnostic assays of HAND and potential preventative and treatment strategies.

 描述（由申请人提供）：HIV-1 已被证明能够引起不良神经并发症。高效抗逆转录病毒疗法 (HAART) 的引入已导致生存率提高、病毒载量减少、CD4 T 细胞计数增加、机会性感染减少。 ，并导致最严重形式的 HIV 相关神经认知障碍 (HAND)、HIV 相关痴呆 (HAD) 的减少。然而，所有形式的 HAND 的总体患病率均有所增加，可能是因为。 HIV-1 感染者在持续感染的情况下寿命更长，除了激活中枢神经系统内的抗病毒免疫反应外，HIV-1 蛋白的产生还通过直接和间接机制导致神经毒性。 Tat 蛋白除了驱动病毒转录外，还充当细胞外神经毒性蛋白、星形胶质细胞和小胶质细胞的激活剂，并影响血脑屏障 (BBB) 的结构和功能。尽管广泛使用了HAART，但除了感染的淋巴细胞外，Tat还可以由感染的单核细胞、小胶质细胞和星形胶质细胞持续产生，这些细胞可以由位于中枢神经系统的HIV-1感染的细胞持续产生，这表明神经系统对这种蛋白质的脆弱性在HAART时代仍然存在。此外，HIV-1 患者的大脑提取物中 Tat 的 mRNA 水平也表现出广泛的序列变异，其准种由许多宿主特异性和共病压力形成。同时维持对复制和感染性以及发病机制至关重要的功能。有关 B 亚型 Tat 遗传变异和 HAND 的研究表明 (i) 在不存在或存在 HAD 的情况下，来自患者的 Tat 序列显示出与神经系统相关的序列聚类。损伤以及起源组织，(ii) HAND 患者脑源性 Tat 序列中的非同义突变率与同义突变率显着高于从无神经系统疾病患者中分离的序列，以及 (iii) 第 74 位和第 74 位的变异100 与从脑源序列中分离出的 Tat 序列相关。重要的是，源自 HAD 患者的 HIV-1 Tat 与更大的神经元死亡相关，这些报告表明 HIV-1 Tat 的多样性遗传可能有助于其建立和发挥作用。鉴于此，本申请的假设是患者来源的 HIV 蛋白 Tat 的遗传变异与神经功能障碍特定相关。为了探索这一假设，具体目标是：(1) 识别和表征多态性。对患有特定程度神经认知障碍的患者进行 HIV-1 Tat 检测；(2) 检查 HIV-1 Tat 多态性在蛋白质-蛋白质分子模型中的结构影响；以及 (3) 检查 Tat 多态性对 BBB 和功能的影响。这些研究将有助于确定 HIV-1 Tat 多态性如何影响 CNS 功能和 HAND 的发展，并为 HAND 诊断分析的开发以及潜在的预防和治疗提供有用的信息。策略。