The Role of HIV Tat-induced SOCS3 in HIV Associated Dementia

HIV Tat 诱导的 SOCS3 在 HIV 相关痴呆中的作用

基本信息

批准号：
7671757
负责人：
Lisa Nowoslawski Akhtar
金额：
$ 3.08万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7671757
关键词：
AIDS Dementia Complex Affect Antiviral Agents Antiviral Response Brain Cells Cessation of life Cognitive Consequences of HIV Cytokine Inducible SH2-Containing Protein Dementia Evaluation Event Family Functional disorder Gene Targeting Goals HIV HIV Infections Human Immune Immune response Immune system In Vitro Incidence Interferons Macaca Mediating Mediator of activation protein Modeling Motor Mus Neuraxis Neurologic Neurons Patients Phosphorylation Play Production Protein Overexpression Proteins Regulation Reporting Role Signal Induction Signal Pathway Signal Transduction Signaling Protein Specificity Stimulus Symptoms United States Viral Work antiretroviral therapy brain tissue cell type combat cytokine experience gene induction in vivo insight macrophage novel pathogen prevent protein expression public health relevance response therapy development

项目摘要

DESCRIPTION (provided by applicant): HIV Associated Dementia (HAD) is a strikingly debilitating neurological consequence of HIV infection. Although its cause is still unclear, it is thought that HIV replication within immune cells of the Central Nervous System (CMS) results in their dysfunction, leading indirectly to neuronal death. While Interferon (IFN) (3, a cytokine mediator of the innate immune response in the brain, has been shown to be effective at preventing HIV replication, the effect is transient. HIV is eventually able to overcome its antiviral effects and resume replication, an event which heralds progression to HAD. Therefore, it is critical that the mechanism by which HIV evades this protective immune response be determined. Recently, numerous viral and bacterial pathogens, including HIV, have been shown to induce the expression of a family of negative regulators of cytokine function, the Suppressors Of Cytokine Signaling (SOCS). The goal of this proposal is to determine whether SOCS protein expression in the HIV-infected brain mediates the loss of IFN(3's ability to suppress HIV replication, and therefore promotes progression to HAD. First, it must be determined whether SOCS expression occurs in the HIV-infected brain. This will be examined in vivo by evaluation of SOCS protein expression in post-mortem HAD brain tissue. In addition, HIV Tat-treatment of CNS-relevant primary human and murine cells will be used in vitro to determine the mechanism of SOCS induction. Second, it must be determined whether SOCS protein expression functions to inhibit IFN(3 signaling, and thereby promote HIV replication in the brain. IFN0 signaling will be examined in vitro, in primary human and murine cells, at the level of STAT phosphorylation, target gene induction, and inhibition of HIV replication. The effect of both SOCS protein overexpression and deficiency will be evaluated to determine whether SOCS expression is sufficient to mediate inhibition of IFN(3's antiviral response. These studies will provide novel insight into the mechanism by which HIV is able to evade the innate immune system in the CNS. PUBLIC HEALTH RELEVANCE: This work seeks to determine whether HIV replication in the brain, and therefore progression to HIV Associated Dementia (HAD), is aided by Suppressor Of Cytokine Signaling (SOCS) proteins. Defining the potential mechanism by which these proteins allows HIV to evade the brain's protective immune response will allow for the development of therapies to strengthen this defense.

描述（由申请人提供）： HIV相关的痴呆（HAT）是HIV感染的神经系统衰弱。尽管其原因尚不清楚，但人们认为中枢神经系统免疫细胞（CMS）内的HIV复制导致其功能障碍，间接导致神经元死亡。虽然干扰素（IFN）（3，是大脑先天免疫反应的细胞因子介体，已被证明有效地预防HIV复制，这种作用是短暂的。艾滋病毒最终能够克服其抗病毒效应并恢复复制，这是一种疾病，因此，这种响应是由此确定的。病原体（包括HIV）已被证明会诱导细胞因子功能的负调节剂的表达，这一建议的抑制因子（SOCS）是SOCS蛋白在HIV感染的人中表达的目的是确定IFN的损失（3）是否抑制了HIV的损失（3感染HIV的大脑。此外，与中枢神经系统相关的原代人和鼠类细胞的HIV TAT治疗将在体外用于确定SOC诱导的机理。其次，必须确定是否SOCS蛋白表达是否功能抑制IFN（3信号传导，从而促进大脑中的HIV复制。在统计磷酸化水平，靶标基因诱导和抑制HIV的效应方面，将在体外检查IFN0信号传导。这些研究将抑制IFN（3的抗病毒反应。3的抗病毒反应。艾滋病毒能够逃避CNS中的先天免疫系统的机制。公共卫生的相关性：这项工作旨在通过抑制抑制抑制性的机制来确定这些作用（确定的机制），这项工作是否可以通过抑制hiv的痴呆症来确定这些蛋白质（确定这些社会），因此确定了这些社会（SICS）的影响。艾滋病毒逃避大脑的保护性免疫反应将使疗法发展以加强这种防御。