HOPE - HIV Obstruction by Programmed Epigenetics
HOPE - 通过编程表观遗传学阻断 HIV
基本信息
- 批准号:10313946
- 负责人:
- 金额:$ 533.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-16 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAddressAdoptedAfricaArchitectureBiologyBloodBrazilCellsCerebrospinal FluidClinicalClustered Regularly Interspaced Short Palindromic RepeatsCommunitiesCommunity Health EducationDNADetectionEndogenous RetrovirusesEnsureEpigenetic ProcessExcisionFaceFailureFoundationsFundingGene SilencingGenome engineeringGiftsGoalsGut associated lymphoid tissueHIVHIV-1HealthHealth ServicesHumanHuman GenomeImmunosuppressionIndustryInfectionIntakeIntegration Host FactorsLearningLeukapheresisLifeLongevityMilitary PersonnelMissionMolecularMorbidity - disease rateMutationMyeloid CellsNational Institute of Allergy and Infectious DiseaseNational Institute of Neurological Disorders and StrokeObstructionPeptide Nucleic AcidsPharmaceutical PreparationsProvirusesPublic HealthResearchResearch PersonnelResearch SupportRiskSamplingSan FranciscoScienceSourceStem cell transplantSuggestionT-LymphocyteTechnologyTestingTissuesToxic effectTranslationsUnited States National Institutes of HealthViralViral Load resultViral reservoirVirionVirusVirus LatencyVirus ReplicationWorkantiretroviral therapyantiviral immunitybasecell typecohortcollaboratorycombinatorialcomorbiditycortistatinexpectationimprovedindustry partnerinhibitor/antagonistinnovationintegration sitelatent HIV reservoirlymph nodesmembermortalitynext generationnovelnovel strategiesorganizational structurepreventprogramsrecombinaserestorationsocial stigmasuccesstoolviral rebound
项目摘要
PROJECT SUMMARY/ABSTACT
After 40 years, a cure for people living with HIV (PLWH) remains both elusive and one of NIAID/NIH’s highest
priorities. Rebound-competent latent reservoir cells persist despite antiretroviral therapy and rekindle infection
due to the lack of efficient proviral silencing. The underlying hypothesis of the HIV Obstruction by Programmed
Epigenetics (HOPE) Collaboratory application is a novel “block-lock-excise” approach—that entails the long-term
durable silencing of viral expression towards permanent excision of the latent provirus—will lead to the
permanent control of the virus in the absence of therapy. A graded transformation of remnant HIV in PLWH is
proposed from latent into silent to permanently defective proviruses, thus emulating and accelerating the natural
path that human endogenous retroviruses have taken in the human genome over millions of years. This
hypothesis was formulated on the basis of 30+ years of dedicated research by HOPE investigators into the
underlying mechanisms of HIV latency, lack of success to date with latency-reversing strategies, recent results
with Tat inhibitor didehydro-Cortistatin A (dCA) and ELITE controllers showing that a successful ‘functional’ HIV
cure could arise if there is a deep silencing of reservoir virus, and the availability of advanced genome-
engineering technologies (Brec1 recombinase, peptide nucleic acids, CRISPR-base editors) for direct delivery
of the final coup de grace: excision of remnant virus for permanent cure. The central hypothesis will be tested in
three Research Focuses (RFs) and five central objectives shared between the three RFs. Specific Aim (RF) 1:
Define mechanistically the durable transcriptional silencing of HIV across all T- and myeloid cell subsets by
combinatorial targeting of key host and viral factors. Specific Aim (RF) 2: Develop and characterize next-
generation HIV silencing approaches in the control of HIV rebound. Specific Aim (RF) 3: Disable the silenced
HIV-1 provirus by targeted genome engineering. Objective 1: Determine the epigenetic architecture of the
integrated provirus at different integration sites that prevents permanent silencing of latent HIV. Objective 2:
Define, at the molecular level, cell types and epigenetic cell states that favor viral rebound. Objective 3: Identify
molecular functions of Tat and host factors that prevent permanent silencing. Objective 4: Learn from HERV
silencing and mutational decay in the human genome. Objective 5: Respond to community expectations around
‘functional’ and ‘classical’ cure approaches. The HOPE Collaboratory partnered with the San Francisco AIDS
Foundation to build a strong art-based community education program and with three primary industry leaders,
Amgen, Sangamo and Constellation, who will provide intellectual and materialistic support. We also engaged
with four clinical cohorts of PLWH for clinical sample analysis in the US, Brazil and Africa. Collectively, the
innovative science, renowned members, collaborative organizational structure and milestone- driven research
plan of the HOPE Collaboratory represents a new and substantive departure from the status quo and promises
a fundamental new approach to HIV Cure strategies.
项目总结/ABSTACT
40年后,对艾滋病毒携带者(PLWH)的治愈仍然难以捉摸,也是NIAID/NIH最高的之一
优先事项。尽管接受了抗逆转录病毒治疗并重新引发感染,但具有反弹能力的潜伏储存库细胞仍然存在
由于缺乏有效的前病毒沉默。人类免疫缺陷病毒程序化阻塞的基本假说
表观遗传学(HOPE)合作实验室应用是一种新的“块-锁-切除”方法--需要长期
持久沉默病毒表达以永久切除潜伏期前病毒-将导致
在没有治疗的情况下永久控制病毒。PLWH中残留HIV的分级转化是
建议从潜伏到沉默到永久有缺陷的普鲁斯,从而模仿和加速自然
人类内源性逆转录病毒在数百万年来进入人类基因组的路径。这
假说是基于HOPE研究人员30多年的专注研究提出的
艾滋病毒潜伏期的潜在机制,潜伏期逆转策略迄今缺乏成功,最新结果
TAT抑制剂二氢皮质酮A(DCA)和精英控制器表明,成功的“功能性”艾滋病毒
如果水库病毒的深度沉默,以及先进基因组的可用性,就可能出现治愈-
用于直接投递的工程技术(Brec1重组酶、肽核酸、基于CRISPR的编辑)
最后的妙招:根治残存的病毒。核心假设将在#年进行检验。
三个研究重点(RFS)和三个RFS共享的五个中心目标。特定目标(RF)1:
从机制上定义艾滋病毒在所有T细胞和髓系细胞亚群中的持久转录沉默
关键宿主和病毒因子的组合靶向。特定目标(RF)2:开发和描述NEXT-
世代HIV沉默方法在控制HIV反弹中的作用。特定目标(RF)3:禁用静音器
靶向基因组工程的HIV-1前病毒。目标1:确定细胞的表观遗传结构
在不同的整合部位整合前病毒,防止潜伏的艾滋病毒永久沉默。目标2:
在分子水平上定义有利于病毒反弹的细胞类型和表观遗传细胞状态。目标3:确定
TAT的分子功能和防止永久沉默的宿主因子。目标4:向Herv学习
人类基因组中的沉默和突变衰退。目标5:回应周围社区的期望
“功能性”和“经典性”治疗方法。希望合作实验室与旧金山艾滋病协会合作
基金会建立了一个强大的以艺术为基础的社区教育计划,并与三位主要的行业领导者,
安进、桑加莫和星座,他们将提供智力和物质上的支持。我们还参与了
在美国、巴西和非洲与PLWH的四个临床队列进行临床样本分析。总体而言,
创新的科学,知名的成员,协作的组织结构和里程碑驱动的研究
希望合作实验室计划代表着与现状和承诺的新的实质性背离
一种根本性的艾滋病毒治疗战略新方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lishomwa C Ndhlovu其他文献
HIV-1 infection induces retrotransposition of LINE-1 elements
- DOI:
10.1186/1742-4690-6-s2-p43 - 发表时间:
2009-09-24 - 期刊:
- 影响因子:3.900
- 作者:
R Brad Jones;Keith E Garrison;Haihan Song;Anton Buzdin;Naveed Anwar;Duncan A Meiklejohn;Lishomwa C Ndhlovu;Douglas F Nixon;Mario A Ostrowski - 通讯作者:
Mario A Ostrowski
Lishomwa C Ndhlovu的其他文献
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{{ truncateString('Lishomwa C Ndhlovu', 18)}}的其他基金
Impact of IL-15 immunotherapy on tissue-specific CD8 T cells to reduce the CNS HIV reservoir seeding and persistence
IL-15 免疫疗法对组织特异性 CD8 T 细胞的影响,以减少中枢神经系统 HIV 储存库的播种和持久性
- 批准号:
10831170 - 财政年份:2023
- 资助金额:
$ 533.6万 - 项目类别:
Defining the Immunogenicity and Efficacy of a Durable BCG Vaccine Strategy Optimized for Preventing TB in Pediatric HIV Infection
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10760444 - 财政年份:2023
- 资助金额:
$ 533.6万 - 项目类别:
Impact of IL-15 immunotherapy on tissue-specific CD8 T cells to reduce the CNS HIV reservoir seeding and persistence
IL-15 免疫疗法对组织特异性 CD8 T 细胞的影响,以减少中枢神经系统 HIV 储存库的播种和持久性
- 批准号:
10476697 - 财政年份:2022
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$ 533.6万 - 项目类别:
HOPE - HIV Obstruction by Programmed Epigenetics
HOPE - 通过编程表观遗传学阻断 HIV
- 批准号:
10625421 - 财政年份:2021
- 资助金额:
$ 533.6万 - 项目类别:
HOPE - HIV Obstruction by Programmed Epigenetics
HOPE - 通过编程表观遗传学阻断 HIV
- 批准号:
10469610 - 财政年份:2021
- 资助金额:
$ 533.6万 - 项目类别:
Harnessing Single Cell Epigenome-wide profiling of Myeloid cells to Compare and Contrast Alzheimer's from HIV-Associated Cognitive Dysfunction
利用骨髓细胞的单细胞表观基因组分析来比较和对比 HIV 相关认知功能障碍引起的阿尔茨海默病
- 批准号:
10569610 - 财政年份:2020
- 资助金额:
$ 533.6万 - 项目类别:
Harnessing Single Cell Epigenome-wide profiling of Myeloid cells to Compare and Contrast Alzheimer's from HIV-Associated Cognitive Dysfunction
利用骨髓细胞的单细胞表观基因组分析来比较和对比 HIV 相关认知功能障碍引起的阿尔茨海默病
- 批准号:
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$ 533.6万 - 项目类别:
Harnessing single cell epigenome-wide profiling of myeloid cells to compare and contrast Alzheimer's from HIV-associated cognitive dysfunction
利用骨髓细胞的单细胞表观基因组分析来比较和对比阿尔茨海默病与艾滋病毒相关的认知功能障碍
- 批准号:
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$ 533.6万 - 项目类别:
Harnessing Single Cell Epigenome-wide profiling of Myeloid cells to Compare and Contrast Alzheimer's from HIV-Associated Cognitive Dysfunction
利用骨髓细胞的单细胞表观基因组分析来比较和对比 HIV 相关认知功能障碍引起的阿尔茨海默病
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$ 533.6万 - 项目类别:
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