Multi-Omics Correlates of Broadly Neutralizing Antibody Efficacy
广泛中和抗体功效的多组学关联
基本信息
- 批准号:10724224
- 负责人:
- 金额:$ 23.25万
- 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:2023-07-11 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:Antibody TherapyCell surfaceCellsCellular ImmunityCellular Indexing of Transcriptomes and Epitopes by SequencingChromatinClinicalClinical TrialsComputer AnalysisDataDoseDrug KineticsEffectivenessGenetic TranscriptionGenomicsHIV-1HumanImmune responseImmunologicsIn SituIndividualInfusion proceduresIntervention StudiesLymphoid TissueMacacaMacaca mulattaMeasuresMolecular ProfilingMucous MembraneMultiomic DataParticipantPhenotypePropertyProteinsProteomicsReportingResistanceResolutionSpecimenTestingTherapeuticTissue SampleTissuesTranscriptVaccine TherapyVaccinesViralViral PhysiologyViral reservoirVirusVirus Replicationanti-viral efficacygastrointestinalinsightlymph nodesmultiple omicsneutralizing antibodynext generationnonhuman primateprotein biomarkerssimian human immunodeficiency virussingle-cell RNA sequencingtranscriptomicsviral DNAviral RNAviral detectionviral rebound
项目摘要
SUMMARY
Accumulating data suggests that administration of broadly neutralizing antibodies (bNAbs) in ART-suppressed,
SHIV-infected nonhuman primates (NHPs) and HIV-1-infected humans can delay viral rebound following ART
discontinuation. However, the mechanism underlying the efficacy of bNAbs remains to be determined. Multiple
mechanisms may contribute to the effectiveness of bNAbs in delaying viral rebound, including direct antiviral
activity against replicating virus, targeting of the replication-competent viral reservoir, and indirect effects such
as augmenting cellular immune responses via the “vaccinal” effect. Understanding the mechanism of action
underlying bNAb efficacy will lead to optimization of these and other HIV-1 cure strategies.
In Project 1, we hypothesize that bNAbs can directly target the viral reservoir in addition to providing
direct antiviral effects, both of which contribute to the observed long-term virologic control following
ART discontinuation. An alternative hypothesis is that bNAbs contribute to long-term antiviral efficacy
by modulating host cellular immunity via the vaccinal effect. To evaluate these hypotheses, we propose
two Specific Aims:
Aim 1. To determine multi-omics correlates of bNAb based virologic control in HIV-1-infected humans.
We will perform a comprehensive virologic, immunologic, and multi-omics analysis of existing clinical specimens
from the T003 study to generate hypotheses regarding correlates of long term vs. short term virologic control.
Aim 2. To define mechanisms of bNAb efficacy in lymphoid tissues in SHIV-infected rhesus macaques.
We will perform interventional studies to test the hypothesis that bNAbs can target the viral reservoir in lymph
nodes and gastrointestinal mucosa in SHIV-infected rhesus macaques.
We will apply cutting-edge, high-throughput, multi-omics profiling platforms detailed in Core B (Multi-Omics
Core) to define the impact of bNAb therapy. We will then integrate the multi-omics data in Core C (Computational
Analysis Core) to generate a comprehensive landscape and regulatory network of the viral reservoir and host
immune responses following bNAb therapy. These data will define the impact of bNAbs on the replication-
competent viral reservoir at an unprecedented level of resolution, which will provide critical insights for next
generation HIV-1 cure efforts.
总结
累积的数据表明,在ART抑制的,
HIV感染的非人灵长类动物(NHP)和HIV-1感染的人类可以延迟ART后的病毒反弹
中止。然而,bNAb功效的潜在机制仍有待确定。多
这些机制可能有助于bNAb延缓病毒反弹的有效性,包括直接抗病毒
抗复制病毒的活性、靶向有复制能力的病毒储库,以及间接作用,
通过“疫苗”效应增强细胞免疫反应。了解作用机制
潜在的bNAb功效将导致这些和其他HIV-1治愈策略的优化。
在项目1中,我们假设bNAb除了提供免疫原性外,还可以直接靶向病毒库。
直接的抗病毒作用,这两种作用都有助于观察到的长期病毒学控制,
停止抗逆转录病毒疗法。另一种假设是bNAb有助于长期抗病毒疗效
通过疫苗效应调节宿主细胞免疫。为了评估这些假设,我们建议
两个具体目标:
目标1.确定HIV-1感染者中基于bNAb的病毒学控制的多组学相关性。
我们将对现有的临床标本进行全面的病毒学、免疫学和多组学分析
从T003研究中得出关于长期与短期病毒学控制相关性的假设。
目标2.明确bNAb在SHIV感染恒河猴淋巴组织中的作用机制。
我们将进行干预性研究,以验证bNAb可以靶向淋巴中的病毒库的假设。
淋巴结和胃肠道粘膜的SHIV感染恒河猴。
我们将应用核心B(多组学)中详细介绍的尖端、高通量、多组学分析平台
核心),以确定bNAb治疗的影响。然后,我们将多组学数据集成到核心C(计算
分析核心),以生成病毒储库和宿主的全面景观和调控网络
bNAb治疗后的免疫反应。这些数据将定义bNAb对复制的影响-
在前所未有的分辨率水平上的合格病毒库,这将为下一个
一代HIV-1治愈的努力。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Dan H. Barouch其他文献
Pharmacokinetic interaction assessment of an HIV broadly neutralizing monoclonal antibody VRC07-523LS: a cross-protocol analysis of three phase 1 trials in people without HIV
- DOI:
10.1186/s12865-025-00687-7 - 发表时间:
2025-02-19 - 期刊:
- 影响因子:2.700
- 作者:
Tariro D. Chawana;Stephen R. Walsh;Lynda Stranix-Chibanda;Zvavahera M. Chirenje;Chenchen Yu;Lily Zhang;Kelly E. Seaton;Jack Heptinstall;Lu Zhang;Carmen A. Paez;Theresa Gamble;Shelly T. Karuna;Philip Andrew;Brett Hanscom;Magdalena E. Sobieszczyk;Srilatha Edupuganti;Cynthia L. Gay;Sharon B. Mannheimer;Christopher B. Hurt;Kathryn E. Stephenson;Laura L. Polakowski;Hans Spiegel;Margaret Yacovone;Stephanie Regenold;Catherine Yen;Jane AG. Baumblatt;Lucio Gama;Dan H. Barouch;Estelle Piwowar-Manning;Richard A. Koup;Georgia D. Tomaras;Ollivier Hyrien;Alison C. Roxby;Yunda Huang - 通讯作者:
Yunda Huang
On-patient medical record and mRNA therapeutics using intradermal microneedles
住院病历与使用皮内微针的信使核糖核酸疗法
- DOI:
10.1038/s41563-024-02115-4 - 发表时间:
2025-02-24 - 期刊:
- 影响因子:38.500
- 作者:
Jooli Han;Maria Kanelli;Yang Liu;John L. Daristotle;Apurva Pardeshi;Timothy A. Forster;Ari Karchin;Brandon Folk;Lukas Murmann;Lisa H. Tostanoski;Sebastian E. Carrasco;Shahad K. Alsaiari;Erika Yan Wang;Khanh Tran;Linzixuan Zhang;Behnaz Eshaghi;Lauren Levy;Sydney Pyon;Charles Sloane;Stacey Qiaohui Lin;Alicia Lau;Collin F. Perkinson;Moungi G. Bawendi;Dan H. Barouch;Frédo Durand;Robert Langer;Ana Jaklenec - 通讯作者:
Ana Jaklenec
Attenuated emMycobacterium tuberculosis/em vaccine protection in a low-dose murine challenge model
减毒鼠伤寒沙门菌疫苗在低剂量小鼠攻击模型中的保护作用
- DOI:
10.1016/j.isci.2023.106963 - 发表时间:
2023-06-16 - 期刊:
- 影响因子:4.100
- 作者:
Samuel J. Vidal;Daniel Sellers;Jingyou Yu;Shoko Wakabayashi;Jaimie Sixsmith;Malika Aid;Julia Barrett;Sage F. Stevens;Xiaowen Liu;Wenjun Li;Courtney R. Plumlee;Kevin B. Urdahl;Amanda J. Martinot;Dan H. Barouch - 通讯作者:
Dan H. Barouch
SIV proviruses seeded later in infection are harbored in short-lived CD4sup+/sup T cells
在感染后期植入的猴免疫缺陷病毒(SIV)前病毒存在于短寿命的CD4<sup>+</sup>T细胞中
- DOI:
10.1016/j.celrep.2025.115663 - 发表时间:
2025-05-27 - 期刊:
- 影响因子:6.900
- 作者:
Narmada Sambaturu;Emily J. Fray;Vivek Hariharan;Fengting Wu;Carolin Zitzmann;Francesco R. Simonetti;Dan H. Barouch;Janet D. Siliciano;Robert F. Siliciano;Ruy M. Ribeiro;Alan S. Perelson;Carmen Molina-París;Thomas Leitner - 通讯作者:
Thomas Leitner
Nonhuman primate antigenic cartography of SARS-CoV-2
非人类灵长类动物对 SARS-CoV-2 的抗原图谱
- DOI:
10.1016/j.celrep.2024.115140 - 发表时间:
2025-01-28 - 期刊:
- 影响因子:6.900
- 作者:
Annika Rössler;Antonia Netzl;Ninaad Lasrado;Jayeshbhai Chaudhari;Barbara Mühlemann;Samuel H. Wilks;Janine Kimpel;Derek J. Smith;Dan H. Barouch - 通讯作者:
Dan H. Barouch
Dan H. Barouch的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Dan H. Barouch', 18)}}的其他基金
Multi-Omics Analysis of Broadly Neutralizing Antibodies and Therapeutic Vaccination
广泛中和抗体和治疗性疫苗的多组学分析
- 批准号:
10724219 - 财政年份:2023
- 资助金额:
$ 23.25万 - 项目类别:
CoVPN LOC Cross-Protocol Infrastructure Supplement for GY15 and GY16
适用于 GY15 和 GY16 的 CoVPN LOC 跨协议基础设施补充
- 批准号:
10571201 - 财政年份:2022
- 资助金额:
$ 23.25万 - 项目类别:
Project 2: Analysis of Reservoir Dynamics in SIV-Infected Rhesus Macaques
项目 2:感染 SIV 的恒河猴的储库动力学分析
- 批准号:
10599365 - 财政年份:2022
- 资助金额:
$ 23.25万 - 项目类别:
Project 2: Analysis of Reservoir Dynamics in SIV-Infected Rhesus Macaques
项目 2:感染 SIV 的恒河猴的储库动力学分析
- 批准号:
10459662 - 财政年份:2022
- 资助金额:
$ 23.25万 - 项目类别:
HIV Vaccines Clinical Trials Network Leadership and Operations Center
HIV 疫苗临床试验网络领导和运营中心
- 批准号:
10311601 - 财政年份:2021
- 资助金额:
$ 23.25万 - 项目类别:
CoVPN 3005 - Efficacy, Immunogenicity, and Safety of SARS-CoV-2 Recombinant Protein Vaccine with Adjuvant in Adults 18 Years of Age and Older
CoVPN 3005 - SARS-CoV-2 重组蛋白疫苗与佐剂对 18 岁及以上成人的功效、免疫原性和安全性
- 批准号:
10415762 - 财政年份:2021
- 资助金额:
$ 23.25万 - 项目类别:
相似海外基金
Mechanisms for cell surface expression of chromatin in apoptotic cells
凋亡细胞中染色质的细胞表面表达机制
- 批准号:
21H03600 - 财政年份:2021
- 资助金额:
$ 23.25万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
New protein engineering-based tools and technologies for characterizing cell surface proteolysis in cancer cells for novel neo-epitope biomarkers and drug targets
基于新蛋白质工程的工具和技术,用于表征癌细胞中的细胞表面蛋白水解,以获得新型新表位生物标志物和药物靶点
- 批准号:
10582604 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
New protein engineering-based tools and technologies for characterizing cell surface proteolysis in cancer cells for novel neo-epitope biomarkers and drug targets
基于新蛋白质工程的工具和技术,用于表征癌细胞中的细胞表面蛋白水解,以获得新型新表位生物标志物和药物靶点
- 批准号:
10371980 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
Interrogation of cell surface antigens on B lineage cells using structurally unique variable lymphocyte receptor antibodies of the evolutionarily distant sea lamprey
使用进化遥远的海七鳃鳗结构独特的可变淋巴细胞受体抗体询问 B 谱系细胞上的细胞表面抗原
- 批准号:
433456 - 财政年份:2020
- 资助金额:
$ 23.25万 - 项目类别:
Operating Grants
Cell Surface Phenotyping Human Primary Cells
人类原代细胞的细胞表面表型分析
- 批准号:
10034909 - 财政年份:2019
- 资助金额:
$ 23.25万 - 项目类别:
Regulation of anti-tumor immune response by cell-surface engineering and development of innovative proliferation method of tumor infiltrating T cells
细胞表面工程调控抗肿瘤免疫反应及肿瘤浸润T细胞创新增殖方法的开发
- 批准号:
19K22951 - 财政年份:2019
- 资助金额:
$ 23.25万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Manufacturing immune cells to treat cancer: characterizing cell-surface interactions
制造免疫细胞来治疗癌症:表征细胞表面相互作用
- 批准号:
526283-2018 - 财政年份:2018
- 资助金额:
$ 23.25万 - 项目类别:
University Undergraduate Student Research Awards
Identification of specific cell surface antigens for separation of neural crest derived cells and its application to bone regenerative medicine
分离神经嵴来源细胞的特异性细胞表面抗原的鉴定及其在骨再生医学中的应用
- 批准号:
18K19655 - 财政年份:2018
- 资助金额:
$ 23.25万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Blocking core fucosylation of PD-1 reduces cell-surface expression and promotes anti-tumor immune responses of T Cells
阻断 PD-1 的核心岩藻糖基化可减少细胞表面表达并促进 T 细胞的抗肿瘤免疫反应
- 批准号:
17K15451 - 财政年份:2017
- 资助金额:
$ 23.25万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Induction of the cell surface-bound TGF-beta on the regulatory T cells by enteric bacteria and its fermentation product.
肠道细菌及其发酵产物在调节性 T 细胞上诱导细胞表面结合的 TGF-β。
- 批准号:
16K09315 - 财政年份:2016
- 资助金额:
$ 23.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)