Heat shock protein 90 and HIV persistence

热休克蛋白 90 和 HIV 持久性

基本信息

批准号：
8663192
负责人：
Cheryl Stoddart
金额：
$ 29.64万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2013-05-17 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8663192
关键词：
1-Phosphatidylinositol 3-Kinase Achievement Acquired Immunodeficiency Syndrome Address Affinity Affinity Chromatography Aftercare C-terminal CD4 Positive T Lymphocytes Cell Death Cell Line Cell Nucleus Cells Chromatin Client Complex DNA Polymerase II Detection Disease remission Epigenetic Process Family Fever Frequencies Genes Genetic Transcription Genomics HIV HIV Infections Heat-Shock Proteins 90 Heat-Shock Response Highly Active Antiretroviral Therapy Histone Deacetylation Human Hyperthermia Immune system Integration Host Factors Interleukin-1 Interleukin-2 Interleukin-6 Lead Length Life Expectancy Lymphocyte Mass Spectrum Analysis Mediating Memory Modeling Molecular Chaperones Mus Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Plasma Positive Transcriptional Elongation Factor B Production Protein Analysis Protein Isoforms Protein Kinase C Proteins Public Health RNA RNA chemical synthesis Reporter Rest Role Sendai virus Signal Transduction Stress TNF gene Temperature Testing Therapeutic Transcript Transcriptional Regulation Viral Viral Load result Viremia Virus Vorinostat bryostatin chaperone machinery chromatin immunoprecipitation chromatin remodeling cytokine expectation inhibitor/antagonist innovation mouse model novel novel therapeutics prevent promoter protein expression public health relevance purge reactivation from latency research study transcription factor treatment strategy ultraviolet irradiation vector

项目摘要

DESCRIPTION: Highly active antiretroviral therapy (HAART) successfully reduces the viral load to below the limit of detection, but HIV replication resumes soon after patients cease therapy. It is believed that a small subset of persistent HIV- infected resting CD4+ T cells are activated in the absence of HAART and contribute to the rebound in patient viral load. This has led to a new treatment strategy that proposes a combination of latency-purging drugs and HAART, with the expectation that activating HIV-infected resting CD4+ T cells will eliminate the persistent viral reservoir by virus-mediated cell death, by the immune system, and by HAART. Reactivation of HIV latency in resting CD4+ T cells can also be induced nonchemically by heat shock. In ongoing experiments, we have found that heat shock protein 90 (Hsp90) is essential for HIV replication and that heat shock (39.5oC) significantly increases HIV infectivity with a simultaneous increase in Hsp90 protein expression. Similar studies by others suggest that reactivation of HIV latency by heat shock is dependent on Hsp90 expression. HIV latency is maintained in resting CD4+ T cells by suppression of the level of virus- specific proteins. Cellular activation results in production of these host factors, but these proteins need to be activated in order to induce HIV reactivation. The active P-TEFb complex and the NF-?B family of transcription factors are essential for HIV reactivation, and these cellular proteins are activated by the Hsp90 chaperone machinery. Similarly, certain chromatin-remodeling proteins that control HIV latency are activated by Hsp90 and lead to HIV reactivation. The examples mentioned above are part of a larger body of work showing that heat shock, and specifically Hsp90, influence HIV replication. Given these observations, we hypothesize that Hsp90 has a functional role in reactivating HIV latency. This hypothesis will be addressed in the experiments of the following Specific Aims: (1) to study how Hsp90 reactivates HIV latency in resting CD4+ T cells, and (2) to identify Hsp90-interacting proteins that reactivate HIV latency. These studies include expressing Hsp90 in untransformed primary human lymphocytes and analyzing the specific Hsp90-interacting proteins that induce HIV reactivation in latently infected resting CD4+ T cells. This hypothesis will be validated in the humanized NSG-BLT mouse model of HIV latency. The objective of this proposal is to identify Hsp90-interacting proteins that reactivate HIV latency, and analysis of these proteins may reveal novel targets for elimination of the latent HIV reservoir.

描述：高度活跃的抗逆转录病毒疗法（HAART）成功地将病毒载量降低至低于检测限，但患者停止治疗后不久就会恢复HIV复制。据信，在没有HAART的情况下激活了一小部分持续性HIV感染的静息CD4+ T细胞，并有助于患者病毒负荷的反弹。这导致了一种新的治疗策略，该策略提出了延迟吸毒和HAART的结合，并期望激活感染HIV的静息CD4+ T细胞将通过免疫系统和Haart消除病毒介导的细胞死亡，并通过病毒介导的细胞死亡以及HAART来消除持续的病毒储层。热休克也可以非化学诱导HIV潜伏期在静止CD4+ T细胞中的重新激活。在正在进行的实验中，我们发现热休克蛋白90（HSP90）对于HIV复制至关重要，热休克（39.5OC）显着增加HIV感染性，同时增加HSP90蛋白表达。其他人的类似研究表明，通过热休克对艾滋病毒潜伏期的重新激活取决于HSP90的表达。通过抑制病毒特异性蛋白质的水平，将HIV潜伏期保持在静息CD4+ T细胞中。细胞激活会导致这些宿主因子的产生，但是需要激活这些蛋白质才能诱导HIV重新激活。活性P-TEFB复合物和NF-？B转录因子家族对于HIV重新激活至关重要，这些细胞蛋白被HSP90伴侣机械激活。类似地，控制HIV潜伏期的某些染色质复制蛋白被HSP90激活并导致HIV重新激活。上面提到的示例是大量工作的一部分，表明热休克，尤其是HSP90会影响HIV复制。鉴于这些观察结果，我们假设HSP90在重新激活HIV潜伏期中具有功能作用。该假设将在以下特定目的的实验中解决：（1）研究HSP90如何在静止的CD4+ T细胞中重新激活HIV潜伏期，以及（2）识别hsp90相互作用的蛋白质，以激活HIV潜伏期。这些研究包括在未转化的原代人淋巴细胞中表达HSP90，并分析特异性的HSP90相互作用蛋白，这些蛋白会诱导潜在感染的静息CD4+ T细胞中诱导HIV重新激活。该假设将在HIV潜伏期的人源化NSG-BLT小鼠模型中得到验证。该建议的目的是确定重新激活HIV潜伏期的HSP90相互作用蛋白，对这些蛋白质的分析可能揭示了消除潜在HIV储量的新靶标。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetically edited CD34+ cells derived from human iPS cells in vivo but not in vitro engraft and differentiate into HIV-resistant cells.

来自人类 iPS 细胞的基因编辑 CD34 细胞在体内但不在体外移植并分化为 HIV 抗性细胞。

DOI：
10.1073/pnas.2102404118
发表时间：
2021
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Morvan,MaeligG;Teque,Fernando;Ye,Lin;Moreno,MaryE;Wang,Jiaming;VandenBerg,Scott;Stoddart,CherylA;Kan,YuetWai;Levy,JayA
通讯作者：
Levy,JayA