Single-cell Proteogenomic profiling of HIV-1 reservoir cells
HIV-1 储存细胞的单细胞蛋白质组学分析
基本信息
- 批准号:10675812
- 负责人:
- 金额:$ 110.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-20 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:AddressAftercareAutologousBindingBiological AssayBiological ProductsBiologyBloodBlood CellsCD4 Positive T LymphocytesCellsChromatinClinicalCollecting CellDNADetectionEffector CellEnvironmentEvaluationEvolutionExposure toGenetic TranscriptionGenomeHIVHIV resistanceHIV-1HeterochromatinHumanImmuneImmune responseImmunityIndividualInfectionInnate Immune ResponseInterventionLeadLocationLymphocyteLymphoid TissueMapsMediatingMolecularPatientsPersonsPharmaceutical PreparationsPhenotypePredispositionProcessPropertyProvirus IntegrationProvirusesRepressionResistanceSurfaceTechnologyTestingTimeTissuesViralViral reservoirWorkadaptive immune responseantiretroviral therapybiomarker identificationchromosomal locationdesigninnovationinsightintegration sitemolecular markernext generation sequencingnovelnovel strategiesperipheral bloodpermissivenesspharmacologicproteogenomicssingle moleculetargeted agentviral resistance
项目摘要
Abstract
HIV-1 reservoir cells are a small subset of CD4 T cells that harbor chromosomally integrated HIV-1 DNA, persist
life-long and represent the major barrier to a cure of HIV-1 infection. For a long time, proviruses in these cells
have been regarded as transcriptionally silent, which permits to escape from host immune recognition and to
resist antiviral host immunity. However, recent studies enabled by single-genome and single-cell analytic
technologies have shown that these cells can frequently be transcriptionally active and be vulnerable to host
immune responses. In line with this observation, our recent work suggested that viral reservoir cells may be
subject to immune-mediated host selection forces that promote elimination of proviruses integrated in permissive
chromatin location supporting active viral transcription, while proviruses in repressive heterochromatin locations
appear to have a selection advantage. In selected cases, such selection forces may, over extended periods of
time, lead to a highly distinct reservoir profile dominated by intact proviruses integrated in heterochromatin
locations; such a highly atypical proviral reservoir landscape may contribute to drug-free control of HIV-1 in elite
and post-treatment-controllers. To better characterize the vulnerabilities and susceptibilities of viral reservoir
cells to host immune cells, we here propose to use a novel single-cell proteogenomic profiling approach designed
to evaluate the surface phenotype and intracellular markers of patient-derived HIV-1-infected cells from blood
and tissues. We hypothesize that viral reservoir cells that persist during antiretroviral treatment are enriched and
selected for phenotypic features conferring repression of proviral transcriptional activity and resistance to
immune-mediated killing, resulting in reduced exposure to and protection from antiviral host effector cells. To
test this hypothesis, we will conduct a detailed phenotypic analysis of HIV-1 reservoirs cells harboring intact and
defective proviruses, focusing on more than 150 individual surface markers and evaluating cells collected ex
vivo from the peripheral blood and from lymphoid tissues of ART-treated persons (specific aim 1). In addition,
we will longitudinally track the evolution of the phenotypic viral reservoir profile, starting in early stages of ART
initiation; simultaneously, the evolution of host immune responses will be analyzed to test the hypothesis that
only a small subset of viral reservoir cells with optimal adaptation to host immune responses can survive long-
term (specific aim 2). Finally, we will evaluate the susceptibility or resistance of HIV-1 reservoir cells to immune-
mediated killing in functional assays and identify surface markers that can be pharmacologically targeted to
reduce resistance of viral reservoir cells to immune-mediated killing (specific aim 3). By providing a detailed
phenotypic characterization of HIV-1 reservoirs cells in direct ex vivo assessments, our studies will be highly
informative for efforts to limit HIV-1 long-term persistence through clinical interventions.
抽象的
HIV-1 储存细胞是 CD4 T 细胞的一小部分,含有染色体整合的 HIV-1 DNA,持续存在
终生,是治愈 HIV-1 感染的主要障碍。很长一段时间以来,这些细胞中的原病毒
被认为是转录沉默的,这允许逃避宿主免疫识别并
抵抗抗病毒宿主免疫。然而,最近的研究通过单基因组和单细胞分析实现
技术表明,这些细胞经常具有转录活性,并且容易受到宿主的攻击
免疫反应。根据这一观察,我们最近的工作表明病毒储存细胞可能是
受到免疫介导的宿主选择力的影响,促进消除整合在许可性中的原病毒
染色质位置支持活跃的病毒转录,而原病毒位于抑制性异染色质位置
似乎具有选择优势。在某些情况下,这种选择力量可能会在很长一段时间内
时间,导致高度不同的储存库特征,以整合在异染色质中的完整原病毒为主
地点;这种高度非典型的原病毒储存库景观可能有助于精英人群中 HIV-1 的无药物控制
和后处理控制器。更好地表征病毒库的脆弱性和易感性
细胞宿主免疫细胞,我们在这里建议使用一种新颖的单细胞蛋白质组分析方法
评估患者血液中 HIV-1 感染细胞的表面表型和细胞内标记
和纸巾。我们假设在抗逆转录病毒治疗期间持续存在的病毒储存细胞被富集并且
选择的表型特征赋予原病毒转录活性的抑制和抗性
免疫介导的杀伤,导致抗病毒宿主效应细胞的暴露和保护减少。到
为了检验这一假设,我们将对携带完整和完整的 HIV-1 储存细胞进行详细的表型分析。
有缺陷的原病毒,重点关注 150 多个单独的表面标记并评估前收集的细胞
来自接受 ART 治疗的人的外周血和淋巴组织的体内(具体目标 1)。此外,
我们将从 ART 的早期阶段开始纵向跟踪表型病毒库的演变
引发;同时,将分析宿主免疫反应的进化,以检验以下假设:
只有一小部分具有最佳适应宿主免疫反应的病毒库细胞可以长期存活
术语(具体目标 2)。最后,我们将评估 HIV-1 储存细胞对免疫的敏感性或抵抗力。
在功能测定中介导杀伤并鉴定可药理学靶向的表面标记
降低病毒库细胞对免疫介导杀伤的抵抗力(具体目标 3)。通过提供详细的
直接离体评估中 HIV-1 储存细胞的表型特征,我们的研究将高度
为通过临床干预措施限制 HIV-1 长期持续存在的努力提供信息。
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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Mathias Lichterfeld其他文献
Mathias Lichterfeld的其他文献
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{{ truncateString('Mathias Lichterfeld', 18)}}的其他基金
High-Definition Characterization of the Persistence and Perturbation of the HIV Reservoir: Project 2
HIV 病毒库的持续性和扰动的高清表征:项目 2
- 批准号:
10469112 - 财政年份:2022
- 资助金额:
$ 110.89万 - 项目类别:
High-Definition Characterization of the Persistence and Perturbation of the HIV Reservoir: Project 2
HIV 病毒库的持续性和扰动的高清表征:项目 2
- 批准号:
10654776 - 财政年份:2022
- 资助金额:
$ 110.89万 - 项目类别:
Pioneering Precision Medicine Approaches for Immune Control of Pediatric HIV-1 Infection
儿科 HIV-1 感染免疫控制的开创性精准医学方法
- 批准号:
10696263 - 财政年份:2021
- 资助金额:
$ 110.89万 - 项目类别:
Pioneering Precision Medicine Approaches for Immune Control of Pediatric HIV-1 Infection
儿科 HIV-1 感染免疫控制的开创性精准医学方法
- 批准号:
10495251 - 财政年份:2021
- 资助金额:
$ 110.89万 - 项目类别:
Mentoring in patient-oriented research to finding a cure for HIV-1 infection
指导以患者为导向的研究,寻找 HIV-1 感染的治疗方法
- 批准号:
10669009 - 财政年份:2021
- 资助金额:
$ 110.89万 - 项目类别:
Mentoring in patient-oriented research to finding a cure for HIV-1 infection
指导以患者为导向的研究,寻找 HIV-1 感染的治疗方法
- 批准号:
10450089 - 财政年份:2021
- 资助金额:
$ 110.89万 - 项目类别:
Pioneering Precision Medicine Approaches for Immune Control of Pediatric HIV-1 Infection
儿科 HIV-1 感染免疫控制的开创性精准医学方法
- 批准号:
10381148 - 财政年份:2021
- 资助金额:
$ 110.89万 - 项目类别:
Mentoring in patient-oriented research to finding a cure for HIV-1 infection
指导以患者为导向的研究,寻找 HIV-1 感染的治疗方法
- 批准号:
10258715 - 财政年份:2021
- 资助金额:
$ 110.89万 - 项目类别:
Novel single genome approaches to determine the mechanisms of HIV latent infection in blood, gut, and lymph nodes
确定血液、肠道和淋巴结中 HIV 潜伏感染机制的新单基因组方法
- 批准号:
10611415 - 财政年份:2019
- 资助金额:
$ 110.89万 - 项目类别:
Novel single genome approaches to determine the mechanisms of HIV latent infection in blood, gut, and lymph nodes
确定血液、肠道和淋巴结中 HIV 潜伏感染机制的新单基因组方法
- 批准号:
10396456 - 财政年份:2019
- 资助金额:
$ 110.89万 - 项目类别:
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