HIV-1 Tat genetic variation impacts NeuroAIDS

HIV-1 Tat 遗传变异影响 NeuroAIDS

• 批准号: 9193105
• 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/9193105
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Adoption; Affect; Amino Acids; Antiviral Agents; Astrocytes; Automobile Driving; Autopsy; Bioinformatics; Biological; 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; Heterogeneity; Highly Active Antiretroviral Therapy; Immunologic Surveillance; Impairment; Individual; Infection; Knowledge; Lead; Length; Link; Lymphocyte; Lymphoid Tissue; Machine Learning; Maps; Messenger RNA; Microglia; Modeling; Molecular Models; Mutation; N-Methyl-D-Aspartate Receptors; National NeuroAids Tissue Consortium; Neuraxis; Neurocognitive Deficit; Neurologic; Neurons; Oligodendroglia; Opportunistic Infections; Pathogenesis; Pathogenicity; Patients; Peripheral; Phylogenetic Analysis; Positioning Attribute; Positive Transcriptional Elongation Factor B; Prevalence; Prevention strategy; Production; Proteins; Reporting; Research; Sequence Analysis; Serum; Severities; Structure; Structure-Activity Relationship; Systems Development; 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 disorder; neuroAIDS; neuron loss; neurotoxic; neurotoxicity; non-demented; novel vaccines; peripheral blood; prediction algorithm; pressure; prevent; protein protein interaction; public health relevance; 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（由适用提供）：HIV-1证明了引起不良神经系统并发症的能力。引入高度活跃的抗逆转录病毒疗法（HAART）导致生存率提高，病毒载量降低，CD4 T细胞计数增加，机会性感染减少，并导致HIV相关的神经认知障碍（手），HIV相关的痴呆症（HIV相关的痴呆症）的最严重形式降低。但是，所有形式的手的总体患病率都增加了，这可能是因为感染HIV-1感染的个体寿命更长。除了激活中枢神经系统内的抗病毒IMMNE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。特别令人感兴趣的是HIV-1反式激活蛋白TAT，除了驱动病毒转录外，它还可以充当细胞外神经毒性蛋白，星形胶质细胞和小胶质细胞的活化剂，并影响血脑屏障（BBB）的结构和功能。 TAT除了受感染的淋巴细胞外，被感染的单核细胞，小胶质细胞和星形胶质细胞释放。 TAT可以由位于中枢神经系统目的地的HIV-1感染细胞不断产生HAART的宽度使用，这表明在HAART时代，对这种蛋白质的神经系统脆弱性持续存在。此外，在患有HAT的个体的脑提取物中，TAT的mRNA水平升高。 HIV-1还显示了许多由许多宿主特异性和合并症压力塑造的准序列的序列变化，同时保持对复制和感染至关重要的功能以及发病机理。关于亚型的遗传变异和手的研究已经证明了（I）患者的TAT序列不存在或存在，已经表明，在神经系统障碍以及起源的组织中，序列的聚类以及（ii）与脑部序列疾病相比，非同步序列的疾病与脑部疾病的疾病相比，非同步序列均高于II的疾病，并且具有较大的tat序列疾病，并且与脑部的同步变化更大，并且与那些人的疾病相比，II的疾病及其疾病的疾病及其（II）疾病的疾病及其（II）的疾病及其（II）的疾病及其（在74和100的位置与从大脑衍生序列分离的TAT序列相关。重要的是，来自HAD患者的HIV-1 TAT与更大的神经元死亡有关。总之，这些报告表明，HIV-1 TAT的遗传多样性可能有助于手的建立和严重性。鉴于此，该应用的假设是HIV蛋白TAT的患者衍生的遗传变异与神经系统障碍特别相关。为了探讨这一假设，具体的目的是：（1）识别和表征来自具有神经认知障碍程度的患者HIV-1 TAT中的多态性； （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； （3）检查TAT多态性对CNS的BBB和细胞的功能影响。这些研究将有助于定义HIV-1 TAT多态性如何影响中枢神经系统的功能和手的发展，并提供用于开发手的诊断暗杀以及潜在预防和治疗策略的信息。