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.
概括
积累的数据表明,在 ART 抑制中施用广泛中和抗体 (bNAb),
感染 SHIV 的非人类灵长类动物 (NHP) 和感染 HIV-1 的人类可以延缓 ART 后的病毒反弹
停产。然而,bNAb 功效的机制仍有待确定。多种的
机制可能有助于 bNAb 延迟病毒反弹的有效性,包括直接抗病毒
对抗复制病毒的活性,针对具有复制能力的病毒库,以及间接影响,例如
通过“疫苗”效应增强细胞免疫反应。了解作用机制
bNAb 的潜在功效将导致这些和其他 HIV-1 治疗策略的优化。
在项目 1 中,我们假设 bNAb 除了提供病毒库外还可以直接靶向病毒库
直接抗病毒作用,这两者都有助于观察到的长期病毒学控制
ART 终止。另一种假设是 bNAb 有助于长期抗病毒功效
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 研究中生成有关长期与短期病毒学控制相关性的假设。
目标 2. 明确 bNAb 在感染 SHIV 的恒河猴淋巴组织中的功效机制。
我们将进行介入研究来检验 bNAb 可以靶向淋巴中病毒库的假设
感染 SHIV 的恒河猴的淋巴结和胃肠粘膜。
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)来定义 bNAb 治疗的影响。然后我们将在 Core C(计算
分析核心)生成病毒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
具有前所未有的分辨率水平的病毒库,这将为下一步提供重要的见解
一代 HIV-1 治愈努力。
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)
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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:
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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
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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
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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
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{{ 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:
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