Quantifying bNAb neutralization of the HIV latent reservoir
定量 HIV 潜伏库的 bNAb 中和作用
基本信息
- 批准号:10676564
- 负责人:
- 金额:$ 46.33万
- 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:2023-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:Antibody TherapyAntiviral AgentsBioinformaticsBiological AssayCD4 Lymphocyte CountCD4 Positive T LymphocytesCell LineCell modelCellsClinicalCloningCoculture TechniquesDNADetectionDevelopmentFlow CytometryHIVHIV-1ImmuneImmune responseIn VitroIndividualInfectionInternationalLaboratoriesLengthLinkMapsMeasuresMediatingNeutralization TestsPatientsPhasePhenotypePropertyProtocols documentationRNARNA SplicingRecording of previous eventsReporterResistanceResolutionSamplingSensitivity and SpecificitySequence AnalysisSiteSortingT-Cell ActivationTestingTherapeutic StudiesTimeTitrationsTranscriptTranscriptional ActivationViralViral Load resultViral reservoirVirusVirus Latencyanalysis pipelinebarrier to testingcohortcombinatorialcostenv Genesgenetic analysisgenetic resistancehigh throughput screeningimmunoregulationin vivolatent HIV reservoirneutralizing antibodynovelresistance mutationsex
项目摘要
Project Summary
Broadly neutralizing antibodies (bNAb) against HIV Env represent a novel class of antivirals that have the
potential to neutralize viral entry, while simultaneously activating non-neutralizing immune effector functions.
However, a major obstacle for their clinical use is identifying the virologically suppressed HIV+ patients that are
best suited for a given bNAb or bNAb combination. Indeed, early-stage therapeutic studies with bNAb have not
found uniform concordance between viral outgrowth assay sequences (in vitro) and the Env resistance
mutations that arise in treated patients in vivo. Our laboratory has developed robust and quantitative flow
cytometry-based assays for neutralization of both cell-free and cell-to-cell infection. We have observed
decreases in the potency and efficacy of Abs using cell-associated versus cell-free HIV-1 neutralization
assays. The detection of these cell-associated phenotypes may be particularly important for cure-based
approaches where functional reactivity of bNAbs against infected cells may be important for in vivo efficacy. To
overcome the limitations of PCR-first based approaches that often identify non-functional Env, we propose the
development of a single cell Viral Outgrowth Neutralization Assay (scVONA) that will be performed in the
presence and absence of bNAb. This scVONA will simultaneously quantify viral latent reservoir sequences and
determine their sensitivity to bNAb. To accomplish this, scVONAs will leverage and enhance a highly sensitive
single cell reporter cell line to detect infection and identify cells to test for neutralization of cell-to-cell spread.
The ultimate readout are single cell flow cytometry measures that enable capture of resistant env genes by
sorting and sequencing insensitive versus sensitive clones. Long read Env sequencing will be employed for
bioinformatic analyses to determine linked sequences that correlate with resistance. Titration of bNAb will also
provide estimated IC50 and sequences may allow a measure of the fraction of sensitive clones. We believe
that scVONA will provide a rapid <2 week readout of neutralization sensitivity and simultaneously provide a
measure of functionally intact env genes for confirmatory analyses, significantly reducing the time, cost and
labor associated with identifying bNAb resistant sequences from HIV+ patient samples.
项目总结
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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BENJAMIN K CHEN其他文献
BENJAMIN K CHEN的其他文献
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{{ truncateString('BENJAMIN K CHEN', 18)}}的其他基金
Single cell transcriptomics of HIV persistence and latency
HIV持续性和潜伏期的单细胞转录组学
- 批准号:
10570277 - 财政年份:2021
- 资助金额:
$ 46.33万 - 项目类别:
Single cell transcriptomics of HIV persistence and latency
HIV持续性和潜伏期的单细胞转录组学
- 批准号:
10721393 - 财政年份:2021
- 资助金额:
$ 46.33万 - 项目类别:
Single cell transcriptomics of HIV persistence and latency
HIV持续性和潜伏期的单细胞转录组学
- 批准号:
10375603 - 财政年份:2021
- 资助金额:
$ 46.33万 - 项目类别:
Single cell transcriptomics of HIV persistence and latency
HIV持续性和潜伏期的单细胞转录组学
- 批准号:
10600389 - 财政年份:2021
- 资助金额:
$ 46.33万 - 项目类别:
Single cell transcriptomics of HIV persistence and latency
HIV持续性和潜伏期的单细胞转录组学
- 批准号:
10258566 - 财政年份:2021
- 资助金额:
$ 46.33万 - 项目类别:
HIV immune evasion and escape through T cell virological synapses
HIV通过T细胞病毒学突触逃避免疫
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10598139 - 财政年份:2020
- 资助金额:
$ 46.33万 - 项目类别:
HIV immune evasion and escape through T cell virological synapses
HIV通过T细胞病毒学突触逃避免疫
- 批准号:
10484093 - 财政年份:2020
- 资助金额:
$ 46.33万 - 项目类别:
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