HIV-1 Associated Dementia: Concomitant Roles of Vpr and Cellular Factors

HIV-1 相关痴呆：Vpr 和细胞因素的伴随作用

基本信息

批准号：
8619524
负责人：
VELPANDI AYYAVOO
金额：
$ 33.91万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-09 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8619524
关键词：
AIDS Dementia Complex Acquired Immunodeficiency Syndrome Affect Amino Acids Apoptosis Apoptotic Astrocytes Autopsy Body Fluids Brain CCL2 gene CXCL10 gene Candidate Disease Gene Cell Line Cell Survival Cell membrane Cell physiology Cells Cognitive Combined Modality Therapy Dementia Development Disease Disease Outcome Environment Event Functional disorder Genes Genetic Polymorphism Genome Genomics Genotype Goals HIV HIV Envelope Protein gp120 HIV-1 Highly Active Antiretroviral Therapy Human In Vitro Incidence Individual Infection Inflammatory Interferons Interleukin-1 Laboratories Lead Mediating Membrane Microglia Modeling Molecular Molecular Models Motor Mutation Natural Killer Cells Nerve Degeneration Neuraxis Neurocognitive Neuronal Dysfunction Neurons Neuropathogenesis Neurotoxins Pathway interactions Patients Peptides Phenotype Property Proteins Proteomics Recombinants Role Signal Pathway Signaling Molecule Structure Structure-Activity Relationship T-Lymphocyte TNF gene Technology Tissue Sample Tropism Variant Viral Viral Proteins Virion Virus Virus Replication base blastomere structure brain tissue cell type chemokine cofactor cytokine deep sequencing design env Gene Products extracellular fitness in vivo inhibitor/antagonist macrophage molecular modeling neuron apoptosis neuron loss novel novel therapeutics public health relevance release factor small hairpin RNA vpr Gene Products

项目摘要

DESCRIPTION (provided by applicant): HIV-1 associated neuropathogenesis is characterized by two distinct observations. The first concerns the notable cognitive and motor dysfunction in HIV-1 infected individuals. The second relates to the lack of infection of neurons by HIV-1. This suggests that the dementia in AIDS patients might be the result of a combination of both direct and indirect effects of HIV-1 encoded proteins (Env, Tat, Nef and Vpr) and host cellular factors. The mechanisms underlying the onset and progression of dementia are poorly understood. The goal of this application is to elucidate the contribution of HIV-1 Vpr to neuropathogenesis. In the infected individuals, Vpr is present in cell-associated, virion-associated and cell and virion-free forms. Further, the ability to traverse through cell membrane endows Vpr the potential to cause damage directly in uninfected bystanders such as neurons. Furthermore, Vpr is also known to indirectly dysregulate bystander cells through cellular factors released from infected target cells. Based on this, we hypothesize that Vpr has the potential to contribute to neuronal apoptosis and dysfunction. To elucidate the molecular events underlying dementia, we propose to analyze the effects of Vpr using appropriate human primary cells in culture as a model. To achieve these goals we propose to: (i) determine the mechanism(s) involved in Vpr mediated neuronal loss and dysfunction directly; (ii) identify the cellular cofactors and neuroinflammatory molecules differentially regulated by Vpr in target cells; and (iii) identify the structure-function relation of Vpr to neuropathogenesis using naturally occurring Vpr variants from CNS compartment.

描述（由申请人提供）：HIV-1相关的神经病发生的特征是两个不同的观察结果。第一个涉及HIV-1感染个体的认知和运动功能障碍。第二个涉及HIV-1缺乏神经元感染。这表明艾滋病患者的痴呆症可能是HIV-1编码蛋白（Env，TAT，NEF和VPR）和宿主细胞因子的直接和间接作用的结果。痴呆症发作和进展的基础机制知之甚少。该应用的目的是阐明HIV-1 VPR对神经病发生的贡献。在受感染的个体中，VPR存在于与细胞相关，与病毒体相关的以及无细胞和无病毒体形式中。此外，通过细胞膜遍历VPR的能力直接在未感染的旁观者（例如神经元）中造成损害的潜力。此外，VPR也已知通过受感染靶细胞释放的细胞因子间接地使旁观细胞失调。基于此，我们假设VPR有可能导致神经元凋亡和功能障碍。为了阐明痴呆症基础的分子事件，我们建议使用培养中适当的人类原代细胞作为模型来分析VPR的效果。为了实现这些目标，我们建议：（i）直接确定VPR介导的神经元丧失和功能障碍涉及的机制；（ii）确定靶细胞中由VPR差异调控的细胞辅助因子和神经炎症分子；（iii）使用CNS室中天然发生的VPR变体确定VPR与神经病发生的结构 - 功能关系。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human immunodeficiency virus type 1 Vpr polymorphisms associated with progressor and nonprogressor individuals alter Vpr-associated functions.

人类免疫缺陷病毒 1 型 Vpr 多态性与进展者和非进展者个体相关，会改变 Vpr 相关功能。

DOI：
10.1099/vir.0.059576-0
发表时间：
2014
期刊：
The Journal of general virology
影响因子：
0
作者：
Hadi,Kevin;Walker,LeahA;Guha,Debjani;Murali,Ramachandran;Watkins,SimonC;Tarwater,Patrick;Srinivasan,Alagarsamy;Ayyavoo,Velpandi
通讯作者：
Ayyavoo,Velpandi

Neuronal apoptosis by HIV-1 Vpr: contribution of proinflammatory molecular networks from infected target cells.