Immuno-Neuropathogenic mechanisms of HIV-1 clade B and C Infection

HIV-1 B 型和 C 型感染的免疫神经病理机制

• 批准号: 8411965
• 负责人: Samikkannu Thangavel
• 金额: $ 6.96万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-12 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8411965
• 关键词: AIDS Dementia Complex; Acids; Acquired Immunodeficiency Syndrome; Affect; Africa; Astrocytes; Attention; Attenuated; Brazil; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Canada; Cells; China; Clinical; Cyclic AMP-Responsive DNA-Binding Protein; Development; Disease; Dopamine Receptor; Enzymes; Functional disorder; Gene Expression; Gene Proteins; Genetic Variation; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Homovanillic Acid; Human; Immune; Incidence; India; Infection; Latin America; Lead; Life; Mediating; Microglia; Nepal; Nerve; Neurocognitive; Neuronal Injury; Neurons; Neuropathogenesis; North America; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; Post-Translational Protein Processing; Protein Kinase; Proteins; Role; Short-Term Memory; Signal Pathway; System; Therapeutic; Tyrosine 3-Monooxygenase; Variant; Virus; Virus Diseases; Western Australia; Western Europe; dopamine transporter; global health; monocyte; peripheral blood; prevent

DESCRIPTION (provided by applicant): Worldwide, approximately 33.3 million people are infected with human immunodeficiency virus type-1 (HIV-1). HIV-1 displays extraordinary genetic variations and the predominant subtype, clade B, is found in North America, Canada, Brazil, Western Europe and Australia whereas clade C is found specifically in Africa, Latin America, China, India and Nepal. Of these, clades B and C represent a large majority (>86%) of circulating HIV-1 variants and more than 56 % of the infection is with clade C. AIDS is often accompanied by immune and neuropathological abnormalities. Dopamine receptors (DRD) and transporter (DAT) are known to play a significant role in immuno-neuropathogenesis of HIV infection. Previous studies suggest that HIV-1 clade variations differentially induce the neuro-immunopathogenic mechanisms. We hypothesize that clade B and C infection exert differential effects on peripheral blood derived monocytes and central nerves system (CNS) cells leading to differential immuno-neuropathogenic effects and the mechanisms may be mediated by dysregulation of Ca2? dependent protein (CaMKs) kinases signaling pathways. Accordingly we will study (Aim #1) the effects of clade B and C virus infections on gene expression and protein modification of dopamine receptor-2 (DRD-2), dopamine transporter (DAT), rate limiting enzyme tyrosine hydroxylase (TH) and level of metabolite homovalinic acid (HVA) by monocytes and primary human CNS cells (astrocytes, neurons, microglial cells), and whether (Aim #2) the mechanism of differential dysregulation of DRD-2 and DAT is mediated by modulation of Ca2?dependent protein kinases (CaMKs) and cAMP response of element-binding protein (CREB) signaling pathways.

描述（由申请人提供）： 全球约有 3330 万人感染 1 型人类免疫缺陷病毒 (HIV-1)。 HIV-1表现出非凡的遗传变异，其主要亚型B分支存在于北美、加拿大、巴西、西欧和澳大利亚，而C分支则特别发现于非洲、拉丁美洲、中国、印度和尼泊尔。其中，B 型和 C 型代表了流行的 HIV-1 变异体的绝大多数 (>86%)，并且超过 56% 的感染是 C 型。艾滋病通常伴有免疫和神经病理学异常。已知多巴胺受体 (DRD) 和转运蛋白 (DAT) 在 HIV 感染的免疫神经发病机制中发挥重要作用。先前的研究表明，HIV-1 进化枝变异会差异性地诱导神经免疫致病机制。我们假设B和C分支感染对外周血来源的单核细胞和中枢神经系统（CNS）细胞产生不同的影响，导致不同的免疫神经病理作用，其机制可能是由Ca2+失调介导的。依赖蛋白 (CaMKs) 激酶信号通路。因此，我们将研究（目标#1）B 型和 C 型病毒感染对多巴胺受体 2 (DRD-2)、多巴胺转运蛋白 (DAT)、限速酶酪氨酸羟化酶 (TH) 和单核细胞和原代人中枢神经系统细胞（星形胶质细胞、神经元、小胶质细胞）代谢物高缬氨酸 (HVA) 的水平，以及是否（目标#2）差异性失调的机制DRD-2 和 DAT 通过 Ca2+ 依赖性蛋白激酶 (CaMKs) 的调节和元件结合蛋白 (CREB) 信号通路的 cAMP 反应来介导。