宿主蛋白Sun2调控HIV潜伏的分子机制

批准号:
31800152
项目类别:
青年科学基金项目
资助金额:
25.0 万元
负责人:
孙玮玮
依托单位:
学科分类:
C0107.病毒学
结题年份:
2021
批准年份:
2018
项目状态:
已结题
项目参与者:
孙丽、蒋清安、王珵珵、樊天娇、闻婧
国基评审专家1V1指导 中标率高出同行96.8%
结合最新热点,提供专业选题建议
深度指导申报书撰写,确保创新可行
指导项目中标800+,快速提高中标率
微信扫码咨询
中文摘要
HIV-1潜伏不能被药物根除是当前AIDS治疗的难点之一。抑制HIV-LTR驱动的前病毒DNA的转录是HIV-1维持潜伏的关键。宿主因素参与前病毒DNA转录调控;抑制性染色质构象是HIV-1转录抑制的关键因素。宿主蛋白Sun2可与核纤层蛋白(Lamin A/C)作用,维持抑制性染色质。前期工作提示:1)Sun2抑制LTR驱动的转录和病毒复制;2)干涉Sun2增强HIV-1潜伏激活;3)HIV-1潜伏激活减弱Sun2与Lamin A/C的作用。因此提出假说,Sun2与Lamin A/C作用,维持抑制性染色质,阻止转录因子招募至LTR,抑制病毒转录,维持HIV-1潜伏。从以下证明假设:1)阐明Sun2-Lamin A/C相互作用对维持HIV-1潜伏和抑制复制的重要性;2)利用HIV-1潜伏模型,探究Sun2通过维持异染色质调控病毒潜伏的分子机制。期望通过揭示HIV潜伏机制,探讨潜伏治疗新策略。
英文摘要
HIV-1 reservoir due to viral latency that cannot be eradicated by antiretroviral therapy represents one of the major obstacles for sterilizing. The silencing of HIV-1-LTR promoter-driven transcription is the critical mechanism for maintaining viral latency. The transcription of HIV-1 proviral DNA can be modulated by host factors, amongst the repressive chromosome or heterochromatin structure is the key for transcriptional silencing. It has been reported that the host protein Sun2 interacting with Lamin maintains the repressive chromosome. Our preliminary studies suggest; 1) Sun2 suppresses HIV-1-LTR-driven transcription; 2) Sun2 maintains HIV-1 latency, as the interference of Sun2 expression promotes HIV-1 reactivation from latency; 3) The HIV-1 reactivation from latency attenuates the interaction of Sun2-Lamin interactions. Therefore, we proposed to delineate the mechanism of Sun2 regulating HIV-1 latency. Our central hypotheses are: the interplay of Sun2-Lamin maintains the repressive chromosome, and blocks the recruitment of host transcriptional factors to HIV-1 LTR-promoter, therefore, HIV-1 transcription is suppressed and viral latency is maintained. We propose two specific aims to test these novel hypotheses: 1) To investigate the modulation of Sun2-Lamin interplay on HIV-1 latency; 2) To determine the mechanism of Sun2 maintaining the repressive chromatin to control latency in detail, using HIV-1 latently infected cells. Accomplishing the proposed studies will provide novel insights into the cellular mechanisms of modulating HIV-1 latency, and facilitate seeking for a new approach to overcome viral latency.
HIV在体内建立潜伏不能被ART治疗清除,是当前AIDS/HIV无法根除的主要原因。HIV-LTR启动子驱动的前病毒DNA的转录,是病毒潜伏感染建立和维持的关键。多种因素如细胞内转录抑制因子的表达、组蛋白与前病毒DNA表观遗传学修饰、染色体重塑等深刻影响HIV-LTR的转录。我们发现Lamin A/C可把SUN2锚定到HIV-LTR的Nuc(核小体)-1和Nuc-2 区域,该区域是LTR驱动转录的关键调控位点;SUN2/Lamin A/C与HIV-LTR的结合,抑制LTR驱动的HIV前病毒基因转录的启始和延伸;机制上,SUN2/Lamin A/C维持了HIV-LTR区域抑制性染色质特性,阻止包括磷酸化的RNA聚合酶II(RNA polymerase II,RNAPII)在内的转录因子至 LTR启动子的招募;干涉SUN2表达,发现LTR Nuc-1和Nuc-2组蛋白修饰H3K4me3显著增加,并发现姐妹染色单体间的距离增加,代表染色质向活跃形式的构象转换;TNF-α激活潜伏HIV或HIV的感染可使SUN2/Lamin A/C相互作用解离,也反过来证实SUN2/Lamin A/C相互作用对HIV复制抑制和潜伏维持作用,提示SUN2/Lamin A/C结合解离是启动HIV复制和潜伏再激活的先决条件。该研究发现调控HIV复制和潜伏的重要宿主蛋白,为抗病毒策略设计提供了宿主新靶点。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
The Establishment of an In Vivo HIV-1 Infection Model in Humanized B-NSG Mice
人源化 B-NSG 小鼠体内 HIV-1 感染模型的建立
DOI:10.1007/s12250-019-00181-6
发表时间:2019-12
期刊:Virologica Sinica
影响因子:5.5
作者:Fan Tian-Jiao;Sun Li;Yang Xian-Guang;Jin Xia;Sun Wei-Wei;Wang Jian-Hua
通讯作者:Wang Jian-Hua
Long noncoding RNA MALAT1 releases epigenetic silencing of HIV-1 replication by displacing the polycomb repressive complex 2 from binding to the LTR promoter
长非编码RNA MALAT1通过取代多梳抑制复合物2与LTR启动子的结合来释放HIV-1复制的表观遗传沉默
DOI:10.1093/nar/gkz117
发表时间:2019-04-08
期刊:NUCLEIC ACIDS RESEARCH
影响因子:14.9
作者:Qu, Di;Sun, Wei-Wei;Wang, Jian-Hua
通讯作者:Wang, Jian-Hua
国内基金
海外基金
