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:10625421
- 负责人:
- 金额:$ 633.43万
- 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:AccelerationAcquired Immunodeficiency SyndromeAddressAdoptedAfricaArchitectureBindingBiologyBloodBrazilCellsCerebrospinal FluidClinicalClustered Regularly Interspaced Short Palindromic RepeatsCommunicationCommunitiesCommunity Health EducationDNADedicationsDetectionEndogenous RetrovirusesEnsureEpigenetic ProcessExcisionFaceFailureFoundationsFundingGene SilencingGenome engineeringGiftsGoalsGut associated lymphoid tissueHIVHIV-1HealthHealth ServicesHumanHuman GenomeImmunosuppressionIndustryInfectionIntakeIntegration Host FactorsLearningLeukapheresisLongevityMilitary PersonnelMissionMolecularMorbidity - disease rateMutationMyeloid CellsNational Institute of Allergy and Infectious DiseaseNational Institute of Neurological Disorders and StrokeObstructionPeptide Nucleic AcidsPersonsPharmaceutical PreparationsProvirus IntegrationProvirusesPublic HealthResearchResearch PersonnelResearch SupportRiskSamplingSan FranciscoScienceSourceStem cell transplantSuggestionTechnologyTestingTissuesToxic effectTranslationsUnited States National Institutes of HealthViralViral Load resultViral reservoirVirionVirusVirus LatencyVirus ReplicationWorkantiretroviral therapyantiviral immunitybasebase editorcell typecohortcollaboratorycombinatorialcomorbiditycortistatinexpectationimprovedindustry partnerinhibitorinnovationintegration 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.
项目概要/摘要
40 年后,艾滋病毒感染者 (PLWH) 的治愈方法仍然难以捉摸,并且是 NIAID/NIH 最高的治疗方法之一
优先事项。尽管进行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细胞仍然存在
由于缺乏有效的原病毒沉默。程序性艾滋病毒阻塞的基本假设
表观遗传学 (HOPE) 合作应用是一种新颖的“区块-锁定-切除”方法,需要长期
病毒表达的持久沉默以永久切除潜伏的原病毒——将导致
在没有治疗的情况下永久控制病毒。 PLWH 中残留 HIV 的分级转化为
提出从潜伏到沉默到永久有缺陷的原病毒,从而模仿和加速自然
数百万年来,人类内源性逆转录病毒在人类基因组中所采取的路径。这
HOPE 研究人员在 30 多年的专门研究的基础上提出了假设
HIV潜伏期的潜在机制、迄今为止潜伏期逆转策略缺乏成功、最新结果
Tat 抑制剂二脱氢皮质抑素 A (dCA) 和 ELITE 控制器表明,成功的“功能性”HIV
如果储存病毒深度沉默,并且先进的基因组技术可用,治愈可能会出现。
用于直接交付的工程技术(Brec1重组酶、肽核酸、CRISPR碱基编辑器)
最后的致命一击:切除残余病毒以获得永久治愈。中心假设将在
三个研究焦点 (RF) 以及三个 RF 共有的五个中心目标。具体目标 (RF) 1:
从机制上定义 HIV 在所有 T 细胞和骨髓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。具体目标 (RF) 2:开发并表征下一步-
一代艾滋病毒沉默方法可控制艾滋病毒反弹。具体目标 (RF) 3:禁用沉默
HIV-1原病毒通过靶向基因组工程。目标 1:确定表观遗传结构
在不同的整合位点整合原病毒,防止潜在艾滋病毒的永久沉默。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:识别
Tat 的分子功能和防止永久沉默的宿主因子。目标 4:向 HEV 学习
人类基因组的沉默和突变衰退。目标 5:响应社区期望
“功能性”和“经典”治疗方法。 HOPE 合作实验室与旧金山艾滋病防治中心合作
基金会建立一个强大的以艺术为基础的社区教育计划,并与三位主要行业领导者合作,
Amgen、Sangamo 和 Constellation 将提供智力和物质支持。我们还参与了
在美国、巴西和非洲对四个感染者临床队列进行临床样本分析。总的来说,
创新科学、知名成员、协作组织结构和里程碑驱动的研究
HOPE合作实验室的计划代表着对现状和承诺的新的实质性背离
艾滋病毒治疗策略的基本新方法。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cell-type specific impact of metformin on monocyte epigenetic age reversal in virally suppressed older people living with HIV.
- DOI:10.1111/acel.13926
- 发表时间:2024-01
- 期刊:
- 影响因子:7.8
- 作者:
- 通讯作者:
Comprehensive synergy mapping links a BAF- and NSL-containing "supercomplex" to the transcriptional silencing of HIV-1.
- DOI:10.1016/j.celrep.2023.113055
- 发表时间:2023-09-26
- 期刊:
- 影响因子:8.8
- 作者:
- 通讯作者:
Not all viruses cause disease: HERV-K(HML-2) in healthy human tissues.
- DOI:10.1371/journal.pbio.3001884
- 发表时间:2022-10
- 期刊:
- 影响因子:9.8
- 作者:
- 通讯作者:
Measurement of Thermal Conductivity and Thermal Diffusivity of Porcine and Bovine Kidney Tissues at Supraphysiological Temperatures up to 93 °C.
- DOI:10.3390/s23156865
- 发表时间:2023-08-02
- 期刊:
- 影响因子:0
- 作者:Bianchi L;Fiorentini S;Gianella S;Gianotti S;Iadanza C;Asadi S;Saccomandi P
- 通讯作者:Saccomandi P
Confounding factors in profiling of locus-specific human endogenous retrovirus (HERV) transcript signatures in primary T cells using multi-study-derived datasets.
- DOI:10.1186/s12920-023-01486-y
- 发表时间:2023-04-03
- 期刊:
- 影响因子:2.7
- 作者:
- 通讯作者:
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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:
$ 633.43万 - 项目类别:
Defining the Immunogenicity and Efficacy of a Durable BCG Vaccine Strategy Optimized for Preventing TB in Pediatric HIV Infection
确定针对儿童 HIV 感染中预防结核病而优化的持久 BCG 疫苗策略的免疫原性和功效
- 批准号:
10760444 - 财政年份:2023
- 资助金额:
$ 633.43万 - 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
- 资助金额:
$ 633.43万 - 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:
10313946 - 财政年份:2021
- 资助金额:
$ 633.43万 - 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:
$ 633.43万 - 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:
$ 633.43万 - 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:
10374058 - 财政年份:2020
- 资助金额:
$ 633.43万 - 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:
10632875 - 财政年份:2020
- 资助金额:
$ 633.43万 - 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:
10795252 - 财政年份:2020
- 资助金额:
$ 633.43万 - 项目类别:
Effects of HIV SIV on unconventional T cells in immunity to M. tuberculosis in pre adolescents
HIV SIV对青春期前结核分枝杆菌免疫中非常规T细胞的影响
- 批准号:
10582697 - 财政年份:2019
- 资助金额:
$ 633.43万 - 项目类别:
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