Mechanisms of Neuro-AIDS by HIV 1B and C Clades

HIV 1B 和 C 进化枝导致神经艾滋病的机制

基本信息

批准号：
8105437
负责人：
MADHAVAN P. NAIR
金额：
$ 33.19万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
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：
2010-07-05 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8105437
关键词：
AIDS Dementia Complex Abbreviations Acquired Immunodeficiency Syndrome Affect Africa South of the Sahara Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Asia Astrocytes Attenuated Brain CCL2 gene Cells Clinical Cognitive Complement Country Dementia Dendritic Cells Developing Countries Development Disease Progression Enzymes Europe Experimental Models Family Future Gene Expression Genetic Variation HIV HIV Infections HIV diagnosis HIV-1 Human Immune response In Vitro India Infection Inflammatory Inositol Institutes Integration Host Factors Interleukin-6 Investigation Kynurenine MAPK14 gene Macrophage Inflammatory Protein-1 Macrophage Inflammatory Proteins Mediating Medical Microglia Military Personnel Minor Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modeling Neuraxis Neurologic Neurons Neuropathogenesis Neurotoxins Nomads Organ Pathogenesis Patients Peptides Phosphotransferases Population Preventive Production Property Protein Kinase Proteins Quinolinic Acid RANTES Recombinants Regulation Reporting Risk Role Signal Transduction Pathway Small Interfering RNA T-Cell Activation TNF gene Therapeutic Time United States Vaccines Viral Virus Virus Diseases Western World chemokine cytokine design frontal lobe indolamine inhibitor/antagonist macrophage member methyl tryptophan mitogen-activated protein kinase p38 monocyte motor disorder neurotoxic novel novel strategies pandemic disease prevent public health relevance stress activated protein kinase stress-activated protein kinase 1 therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The predominant HIV-1 subtype found in US and Western World is clade B, which differs significantly from clade C that exists in sub-Saharan Africa and Asia. Estimates suggest that out of about 33.2 million people infected with HIV-1, about 60% of the infection is with clade C alone and HIV-1C infection is rapidly spreading to other parts of the world. AIDS is often accompanied by neuropathological abnormalities. Current understandings of HIV-1 neuropathogenesis emanate from B clade from U.S and Western countries and very little information is available on neuropathogenesis of C clade. We hypothesize that clade B and C exert differential effects on CNS cells leading to differential neuropathogenesis and the mechanisms may be mediated by dysregulation of mitogen activated protein (MAP) kinases signal transduction pathways. Accordingly we will study for the first time :(Aim #1a) the effects of in vitro infection with clade B and C virus on production and gene expression of pro-inflammatory cytokines (TNF1 & IL-6), chemokines (MCP-1 & RANTES), and neurotoxin (IDO) by primary monocytes and CNS cells (astrocytes, microglial cells) and examine (Aim #1b), whether the mechanism of differential dysregulation induced by clade specific virus infection is mediated by modulation of mitogen activated protein (MAP) kinases signal transduction pathways. Further these in vitro infection studies will be compared, correlated and complemented with ex vivo studies (Aim #2) using monocytes from HIV-1B infected subjects being studied in Miami and HIV-1C infected subjects being studied at the collaborating institute in India. The results emanating from these studies may a) unravel the differential effect of clade specific infection on neuropathogenesis, b) help to develop therapeutically useful agents which could attenuate or prevent the neuropathogenesis associated with clade specific HIV-1 infection and c) design novel strategies to develop preventive and therapeutic global vaccines that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States where non B subtypes have been recently reported in migrant populations and among our military personals. PUBLIC HEALTH RELEVANCE: This application has significant relevance to the purpose of the PA-07-089. Using both in vitro infection and ex vivo models, this project will study for the first time the production and gene expression of neuropathogenic molecules associated with HIV-1B and HIV-C infection. Identification of the mechanisms of clade specific neuropathogenesis will help to design novel strategies to prevent neuropathogenesis in HIV infected subjects and can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States.

描述（由申请人提供）：在美国和西方世界发现的主要 HIV-1 亚型是 B 型，它与撒哈拉以南非洲和亚洲存在的 C 型有显着差异。据估计，在约 3320 万名 HIV-1 感染者中，约 60% 的感染仅感染 C 分支，并且 HIV-1C 感染正在迅速传播到世界其他地区。艾滋病常常伴有神经病理学异常。目前对 HIV-1 神经发病机制的理解源自美国和西方国家的 B 进化枝，而关于 C 进化枝的神经发病机制的信息很少。我们假设进化枝 B 和 C 对 CNS 细胞产生不同的影响，导致不同的神经发病机制，其机制可能是通过丝裂原激活蛋白 (MAP) 激酶信号转导途径的失调介导的。因此，我们将首次研究：（目标 #1a）B 型和 C 型病毒体外感染对促炎细胞因子（TNF1 和 IL-6）、趋化因子（MCP-1 和RANTES）和神经毒素（IDO）由原代单核细胞和中枢神经系统细胞（星形胶质细胞、小胶质细胞）进行检测（目标#1b），是否由进化枝特异性诱导的差异失调机制病毒感染是通过调节丝裂原激活蛋白（MAP）激酶信号转导途径介导的。此外，这些体外感染研究将与来自迈阿密正在研究的 HIV-1B 感染受试者和印度合作研究所正在研究的 HIV-1C 感染受试者的单核细胞的离体研究（目标#2）进行比较、关联和补充。这些研究的结果可能a)揭示进化枝特异性感染对神经发病机制的不同影响，b)有助于开发治疗上有用的药物，可以减轻或预防与进化枝特异性HIV-1感染相关的神经发病机制，c)设计新的策略开发预防性和治疗性全球疫苗，可诱导针对多进化枝或重组大流行性 HIV-1 感染的跨进化枝抗病毒免疫反应，这种感染目前包括美国在内的世界各地，最近报告了非 B 亚型在移民人口和我们的军人中。公共卫生相关性：本申请与 PA-07-089 的目的具有重要相关性。该项目将利用体外感染和离体模型，首次研究与 HIV-1B 和 HIV-C 感染相关的神经致病分子的产生和基因表达。鉴定进化枝特异性神经发病机制将有助于设计新的策略来预防 HIV 感染者的神经发病机制，并可诱导针对目前包括美国在内的世界各地面临的多进化枝或重组大流行 HIV-1 感染的跨进化枝抗病毒免疫反应。