Project 2: Delineating virus and host cell-derived biomarkers predicting time to HIV rebound after treatment interruption
Project 2: Delineating virus and host cell-derived biomarkers predicting time to HIV rebound after treatment interruption
批准号:
10223996
负责人:
Warner C. Greene
金额:
$76.27万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-08-08 至 2023-07-31
关键词:
AftercareAntiviral AgentsApoptosisAutomobile DrivingBioinformaticsBiological AssayBiological MarkersBiological ProcessBiostatistics CoreBloodBlood CellsBlood specimenCASP1 geneCD4 Positive T LymphocytesCell TherapyCellsChemicalsChronicCleaved cellDNADataData SetDisease remissionEnsureFutureGene Expression ProfileGene Expression ProfilingGenesGeneticGoalsGoldHIVHourImmuneIndividualInflammationInterleukin-1 betaInterleukin-15Interleukin-18InterruptionLengthLeukapheresisLibrariesLogisticsMaintenanceMeasurementMeasuresMediatingMediator of activation proteinMessenger RNAMicroRNAsMorbidity - disease ratePatientsPeripheral Blood Mononuclear CellPlasmaPopulationPositioning AttributeProcessProductionProteinsProvirusesRNAResearchRestRiskScientistSurrogate EndpointT memory cellT-LymphocyteTestingTherapeuticTherapeutic InterventionTimeTissuesUnited States National Institutes of HealthViralViral Load resultViremiaVirusWorkacute infectionantiretroviral therapyantiviral immunitybasechronic infectionclinical decision-makingcohortcomplex datacostcurative treatmentscytokinedesigndigitaldrug developmentexhaustionextracellular vesiclesinflammatory markerinsightlatent HIV reservoirmemory CD4 T lymphocytemiRNA expression profilingmortalitynovelpatient subsetspotential biomarkerpredictive markerprogrammed cell death protein 1research clinical testingspecific biomarkerstranscriptome sequencingviral DNAviral RNAviral reboundvolunteer
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
Although antiretroviral therapy (ART) inhibits HIV replication and decreases morbidity and mortality, it
does not cure. Interruption of ART is routinely followed by viral rebound springing from a small but durable
reservoir of latently infected, long lived, memory CD4 T cells. New chemical-, immune- and gene-and cell-
based therapies are now being developed that will be aimed at eradicating this reservoir (difficult to achieve) or
reducing its size and boosting boosting antiviral immunity sufficiently that ART can be safely stopped without
high level viral rebound (functional cure). The search for curative therapies would be greatly facilitated by the
availability of a set of robust biomarkers that can accurately predict whether a specific therapeutic is effective
or not. Such biomarkers could help ensure that only the most promising candidates advance to analytic
treatment interruption––the current gold standard for clinical testing of cure therapeutics. ATI studies need to
be minimized because they are inherently costly, logistically challenging and create potential risks for patients
during viral rebound. These biomarkers might also provide key insight into what biological processes are most
promising for attacking the reservoir and achieving the desired delay in time to rebound. We hypothesize that
highly robust virus-specific and host–specific biomarkers can be identified in blood that accurately predict the
duration of viral remission after treatment interruption as well as impending viral rebound.
To pursue identification of both virus- and host-directed biomarkers, blood samples from 125 HIV
infected subjects (both treated during acute and chronic infection) obtained before ATI and after viral rebound
will be analyzed by three different approaches: (1) Resting blood CD4 T cells will be tested with a novel digital
droplet PCR assay (IPDA) that selectively detects intact proviral DNA in the reservoir––these intact viruses
represent the key small fraction of the proviruses in the reservoir that are replication competent and thus able
to drive viral rebound. Low IPDA results prior to ATI could be associated with long times to viral rebound; this
assay can be performed in 6 hours and only requires the equivalent of a 20 ml blood draw; (2) RNA from both
CD4 T and non-CD4 T cells will be subjected to RNA-Seq and miRNA-Seq analyses to identify patterns of
gene expression associated with markedly delayed or accelerated times to viral rebound and (3) Measurement
of pyroptotic inflammatory markers in cells and plasma as biomarkers predicting rapid loss of viral control or
impending viral rebound during ATI. The complex data sets generated by RNA-Seq will analyzed with the help
of the Bioinformatics and Biostatistics core. This project will also closely interface with both Projects 1 and 2
where complementary approaches will be pursued searching for biomarkers in blood cells and in plasma or
circulating extracellular vesicles. By careful execution of this comprehensive virus- and host-directed search,
our project team should be strongly positioned to discover a robust set of new biomarkers that could truly
galvanize future HIV cure research.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Exploring HIV-associated Neurocognitive Disorder (HAND) and HIV Latency at the Single Cell Level in Cerebral Organoids
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批准号:10237149
-
项目类别:
-
资助金额:$70.8万
-
财政年份:2019
-
负责人:Warner C. Greene
-
依托单位:
Exploring HIV-associated Neurocognitive Disorder (HAND) and HIV Latency at the Single Cell Level in Cerebral Organoids
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批准号:10006808
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项目类别:
-
资助金额:$70.8万
-
财政年份:2019
-
负责人:Warner C. Greene
-
依托单位:
Assessing the root causes of chronic inflammation in HIV-infected individuals using drugs of abuse
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批准号:9761514
-
项目类别:
-
资助金额:$71.45万
-
财政年份:2017
-
负责人:Warner C. Greene
-
依托单位:
Core A: Administrative Core
-
批准号:10223992
-
项目类别:
-
资助金额:$10.11万
-
财政年份:2017
-
负责人:Warner C. Greene
-
依托单位:
Exploiting the Host-HIV Interface To Identify Biomarkers Predicting Time to Viral Rebound after Treatment Interruption
-
批准号:9754763
-
项目类别:
-
资助金额:$168.71万
-
财政年份:2017
-
负责人:Warner C. Greene
-
依托单位:
HIV without AIDS: A Radically Different Approach to Help the Developing World
-
批准号:9503875
-
项目类别:
-
资助金额:$16.62万
-
财政年份:2013
-
负责人:Warner C. Greene
-
依托单位:
HIV without AIDS: A Radically Different Approach to Help the Developing World
-
批准号:8606334
-
项目类别:
-
资助金额:$95.5万
-
财政年份:2013
-
负责人:Warner C. Greene
-
依托单位:
HIV without AIDS: A Radically Different Approach to Help the Developing World
-
批准号:8856536
-
项目类别:
-
资助金额:$94.07万
-
财政年份:2013
-
负责人:Warner C. Greene
-
依托单位:
HIV-Induced CD4 T-Cell Depletion: An Innate Host Defense Gone Awry?
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批准号:8411054
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项目类别:
-
资助金额:$32.85万
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财政年份:2012
-
负责人:Warner C. Greene
-
依托单位:
HIV-Induced CD4 T-Cell Depletion: An Innate Host Defense Gone Awry?
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批准号:8500196
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项目类别:
-
资助金额:$17.64万
-
财政年份:2012
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负责人:Warner C. Greene
-
依托单位:
Identification Novel Host Factors Regulating HIV Latency
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批准号:8326773
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项目类别:
-
资助金额:$42.36万
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财政年份:2011
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负责人:Warner C. Greene
-
依托单位:
Administrative Core
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批准号:7684936
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项目类别:
-
资助金额:$10.87万
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财政年份:2009
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负责人:Warner C. Greene
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依托单位:
Regulation and Action of APOBEC3G
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批准号:7846488
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项目类别:
-
资助金额:$1.31万
-
财政年份:2009
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负责人:Warner C. Greene
-
依托单位:
NF Kappa Beta and the Regulation of HIV Latency
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批准号:7899482
-
项目类别:
-
资助金额:$29.28万
-
财政年份:2009
-
负责人:Warner C. Greene
-
依托单位:
Viral and Host Factors Promoting Male-to-Female Transmission of HIV
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批准号:7684924
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项目类别:
-
资助金额:$33.23万
-
财政年份:2009
-
负责人:Warner C. Greene
-
依托单位:
Effects of Menopause on T-cell Immunity in HIV-Infected Women
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批准号:7555088
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项目类别:
-
资助金额:$39.0万
-
财政年份:2008
-
负责人:Warner C. Greene
-
依托单位:
Effects of Menopause on T-cell Immunity in HIV-Infected Women
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批准号:7690943
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项目类别:
-
资助金额:$14.63万
-
财政年份:2008
-
负责人:Warner C. Greene
-
依托单位:
Regulation and Action of APOBEC3G
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批准号:7083556
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项目类别:
-
资助金额:$46.87万
-
财政年份:2005
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负责人:Warner C. Greene
-
依托单位:
Regulation and Action of APOBEC3G
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批准号:7005092
-
项目类别:
-
资助金额:$41.08万
-
财政年份:2005
-
负责人:Warner C. Greene
-
依托单位:
Regulation and Action of APOBEC3G
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批准号:7414017
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项目类别:
-
资助金额:$52.12万
-
财政年份:2005
-
负责人:Warner C. Greene
-
依托单位:
海外基金