Recognition of HIV by the Inflammasome Signaling Complex

炎症小体信号复合体对 HIV 的识别

基本信息

批准号：
9319096
负责人：
Michael Anand Chattergoon
金额：
$ 19.63万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319096
关键词：
Acquired Immunodeficiency Syndrome Adaptor Signaling Protein Address Age Anti-Inflammatory Agents Anti-inflammatory Antiviral Response Bacterial Infections Binding Cardiovascular Diseases Cell Lineage Cells Chronic Chronic Kidney Failure Complex Cytoplasm Detection Development Diabetes Mellitus Disease Disease Outcome Endocrine System Diseases Endocytosis Endosomes Engineering Environment Event Future Genetic Transcription HIV HIV Infections HIV-1 Highly Active Antiretroviral Therapy Immune response Immunosuppression Incidence Individual Infection Inflammasome Inflammation Inflammatory Inflammatory Response Interferon Type I Interleukin-1 Interleukin-18 Intervention Invaded Kidney Diseases Lactamase Ligands Liver diseases Longevity Lysosomes Malignant Neoplasms Measures Medical Methods Modeling Morbidity - disease rate Osteoporosis Pathogenesis Persons Plasma Preparation Process Production Quantitative Reverse Transcriptase PCR RNA Interference RNA Viruses Risk Role Signal Pathway Signal Transduction Stimulus Sum System TNF gene Testing Therapeutic Intervention Toll-like receptors Viral Virion Virus Virus Diseases Work cytokine extracellular immune activation improved inhibitor/antagonist microbial monocyte mortality nervous system disorder novel pathogen public health relevance response uptake

项目摘要

DESCRIPTION (provided by applicant): HIV infection causes significant morbidity and mortality worldwide. Highly active antiretroviral therapy has dramatically reduced the risk of AIDS, opportunistic illnesses and mortality directly related to immune suppression. However, with the increased longevity of HIV infected persons, it is now evident that they are at increased risk of developing a variety of non-AIDS conditions including cardiovascular, renal, endocrine and neurologic diseases. A growing body of evidence implicates chronic inflammation and immune activation in the development of these non-AIDS conditions. We have shown that inflammasome activation as measured by interleukin-18 (IL-18) production occurs during both HIV and other chronic viral infections. Plasma from infected subjects as well as purified virus preparations stimulate monocytes to produce IL-18. We hypothesize that such viruses induce chronic low-level immune activation by sustaining abnormal inflammasome activity in monocyte lineage cells. This proposal addresses the mechanism by which RNA viruses capable of establishing chronic infections stimulate the inflammasome complex in monocytes regardless of whether they directly infect these cells. We will (1) determine whether Toll-like receptors, which have been previously shown to activate inflammasomes during bacterial infection, also recognize and activate inflammasomes during viral infections. (2) We will examine how the extracellular cytokine environment alters inflammasome activity and; (3) study the role of virus uptake by endocytosis in inflammasome activation. This work will enhance our understanding of immune activation caused by these important viruses. A clear understanding of this process will have implications for managing and treating both the primary viral infection and the co-morbid medical conditions, which are often exacerbated by prolonged immune activation.

描述（由申请人提供）：HIV 感染在全世界范围内导致显着的发病率和死亡率。高效抗逆转录病毒治疗已显着降低了艾滋病、机会性疾病和与免疫抑制直接相关的死亡率的风险。然而，随着艾滋病毒感染者寿命的延长，他们患各种非艾滋病疾病的风险明显增加，包括心血管、肾脏、内分泌和神经系统疾病。越来越多的证据表明慢性炎症和免疫激活与这些非艾滋病疾病的发展有关。我们已经证明，在 HIV 和其他慢性病毒感染期间，通过白细胞介素 18 (IL-18) 的产生来测量炎症小体的激活。来自受感染受试者的血浆以及纯化的病毒制剂刺激单核细胞产生 IL-18。我们假设此类病毒通过维持单核细胞谱系细胞中异常的炎性体活动来诱导慢性低水平免疫激活。该提案阐述了能够建立慢性感染的RNA病毒刺激单核细胞中的炎性复合体的机制，无论它们是否直接感染这些细胞。我们将（1）确定Toll样受体（之前已被证明在细菌感染期间激活炎症小体）是否也在病毒感染期间识别并激活炎症小体。 (2) 我们将研究细胞外细胞因子环境如何改变炎症小体活性； (3)研究内吞作用摄取病毒在炎症小体激活中的作用。这项工作将增强我们对这些重要病毒引起的免疫激活的理解。清楚地了解这一过程将对管理和治疗原发性病毒感染和共病医疗状况产生影响，这些疾病往往因长期免疫激活而加剧。