The HUSH complex in HIV-1 latency
The HUSH complex in HIV-1 latency
批准号:
10176390
负责人:
JEREMY LUBAN
金额:
$78.33万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-01 至 2024-06-30
关键词:
ATAC-seqAcquired Immunodeficiency SyndromeAnti-HIV AgentsCD34 geneCD4 Positive T LymphocytesCell Culture TechniquesCell LineCellsChromatinClinicalClone CellsComplementary DNAComplexDNADNA BindingDNA-Binding ProteinsDevelopmentEvaluationExcisionExhibitsFoundationsGene Expression RegulationGene SilencingGenesGenetic TranscriptionGoalsHIV-1HarvestHematopoieticHematopoietic stem cellsHeterogeneityHumanHuman ChromosomesImmuneImmune systemIndividualInfectionIntegration Host FactorsKineticsMonitorMusPharmaceutical PreparationsPhenotypePhylogenyPlayPrimate LentivirusesProteinsProvirusesReportingResistanceRetrotransposonRoleSETDB1 geneStimulusTranscriptional RegulationUmbilical Cord BloodUrsidae FamilyViralViremiaVirusantiretroviral therapyexperimental studygenetic elementhumanized mouseimprovedin vivoloss of functionmemory CD4 T lymphocytemouse modelnovel strategiespreservationpreventreconstitutionrecruitresponsetooltranscription factortranscriptome sequencingvpr Gene Products
中文摘要
项目摘要/摘要:
目前的抗HIV-1治疗方法可以防止艾滋病的进展,但不能治愈感染。HIV-1的治疗方法持续很长时间。
记忆中的CD4和T细胞就像一个转录上沉默的前病毒,在那里它是被免疫系统和免疫系统检测不到的。
因此,我们对根除有抵抗力。最近,我们有报道称,灵长类动物对免疫缺陷病毒、VPX和VPR具有抵抗力。
蛋白质可以通过降解人类沉默中心的前三种主要蛋白质来激活HIV-1和前病毒转录。
(嘘)很复杂。由于大量CD4和T细胞中的沉默和复杂信号的中断,导致HIV-1的转录水平增加。
提供了人类免疫缺陷病毒-1在传播感染过程中的运动和动力学模型,这表明这种沉默的复合体在治疗中发挥着主导作用。
在HIV-1中,前病毒是沉默的。尽管如此,对单个克隆的检查结果显示,对病毒的反应存在异质性。
沉默、干扰和不一致的相关性与已知的沉默和因素,如SETDB1。Aim 1%将继续存在。
确定对HIV-1和前病毒的复杂沉默能力的要求。这套设备包括CD-4和T细胞克隆。
携带HIV-1病毒的前病毒将不会表现出一系列的保密和反应能力,也不会受到功能丧失的影响。
屏幕需要识别主持人沉默的因素,这些因素可以区分具有不同保密表型的克隆。例如,这些因素。
我们将独立研究对前病毒转录基因和前病毒染色质基因特征的影响。
这些实验,我们可以期待他们能更好地理解秘密是如何被招募来,保持和维持转录的。
人类免疫缺陷病毒(HIV-1)病毒的沉默作用。我们将继续研究人类免疫缺陷病毒(HIV-1)在人类免疫缺陷病毒(CD4-T)中的沉默作用。
转录调节和转录发育。沉默复合体的干扰激活了特定细胞中LINE-1的表达。
台词引发了人们对保密和复杂网络中断可能造成的后果的质疑。
染色质图谱分析也将在原代和人类的CD4+T细胞上进行,在这些细胞中,可以隐藏复杂的蛋白质组分。
中断。特别是逆转座子基因的表达增加是意料之中的,但也包括免疫相关基因的增加。
与HIV-1、DNA和DNA标志物相关的是,它们可能被用来进一步监测和掩盖细胞中复杂的DNA活动。
转录因子和基序在丢失的ATAC--Seq峰值内的基序,将有助于识别可能招募的DNA结合蛋白。
这个复合体。这个复合体也会被脐带血和人类外周血中的CD34和造血干细胞所干扰。
细胞被用来在小鼠体内重新构建一种新的免疫系统。这些实验将不会告诉我们是否会保持沉默。
复杂的细胞对人类的造血系统发育至关重要,尤其是对CD_4~+T细胞的作用。
我们将评估封口剂对体内HIV-1潜伏期的影响,以及封口剂的药效。
将用从HIV-1中提取的CD4和T细胞来检查HIV-1病毒前病毒和重新激活病毒的灭活情况。
接受抗HIV-1和抑制性药物治疗的患者和来自人源化小鼠的药物。这些研究预计将继续下去。
提高对HIV-1转录调控的机械性理解,帮助预测转录水平。
在给定前病毒的情况下,我们将开发新的新的治疗方法,以便在更广泛的临床应用背景下更好地干扰人类免疫缺陷病毒-1前病毒的传播。
而且,更广泛地说,这将增加对基因和监管的基本了解。
英文摘要
Project Summary/Abstract
Current anti-HIV-1 therapies prevent progression to AIDS but do not cure infection. HIV-1 persists in long-lived
memory CD4+ T cells as a transcriptionally silent provirus, where it is undetectable by the immune system, and
therefore resistant to extirpation. Recently, we reported that primate immunodeficiency virus Vpx and Vpr
proteins activate HIV-1 provirus transcription by degrading the three proteins of the human silencing hub
(HUSH) complex. Disruption of the HUSH complex in bulk CD4+ T cells increased transcription from HIV-1
proviruses and kinetics of HIV-1 spreading infections, indicating that the HUSH complex plays a dominant role
in HIV-1 provirus silencing. Nonetheless, examination of individual clones showed heterogeneity in response to
HUSH disruption, and inconsistent correlation with known silencing factors such as SETDB1. Aim 1 will be to
identify requirements for HUSH complex silencing of the HIV-1 provirus. Sets of CD4+ T cell clones
bearing HIV-1 proviruses that exhibit a range of HUSH responsiveness will be subjected to loss-of-function
screens to identify host silencing factors that distinguish clones with different HUSH phenotypes. Such factors
will be characterized independently for effects on provirus transcription and provirus chromatin features. From
these experiments we expect to better understand how HUSH is recruited to, and maintains transcriptional
silencing of, HIV-1 proviruses. Aim 2 will be to examine the role of the HUSH complex in CD4+ T cell
transcription and development. Disruption of the HUSH complex activates LINE-1 expression in certain cell
lines raising questions about possible consequences of HUSH complex disruption. Global transcription and
chromatin profiling will be performed on primary human CD4+ T cells in which HUSH complex components are
disrupted. Increased expression of particular retrotransposons is expected, but also immune-related genes of
relevance to HIV-1, and markers that may be used to monitor HUSH complex activity in cells. Examination of
transcription factor motifs within lost ATAC-Seq peaks will aid identification of DNA-binding proteins that recruit
the HUSH complex. The HUSH complex will also be disrupted in cord blood human CD34+ hematopoietic stem
cells used to reconstitute an immune system in mice. These experiments will tell us whether the HUSH
complex is essential for human hematopoietic development generally or for CD4+ T cells specifically. Aim 3
will assess the contribution of the HUSH complex to HIV-1 latency in vivo. The effect of HUSH complex
inactivation on HIV-1 provirus reactivation will be examined with CD4+ T cells harvested from HIV-1+
individuals on anti-HIV-1 suppressive therapy and from humanized mice. These studies are expected to
improve mechanistic understanding of HIV-1 transcriptional regulation, help prognosticate the transcriptional
status of a given provirus, develop new approaches for disrupting the HIV-1 provirus in the clinical context,
and, more generally, increase fundamental understanding of gene regulation.
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