Assessing the Risk of SARS-CoV-2 Remdesivir Resistance
评估 SARS-CoV-2 瑞德西韦耐药性风险
基本信息
- 批准号:10442701
- 负责人:
- 金额:$ 20万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVActive SitesAnimal ModelAntiviral AgentsAntiviral TherapyAntiviral resistanceBindingBinding SitesBiochemicalBiological AssayCOVID-19COVID-19 monitoringCOVID-19 pandemicCOVID-19 patientCOVID-19 treatmentCell Culture TechniquesCellsCessation of lifeClinicClinicalCollectionComplementCoronavirusDataDexamethasoneDiseaseDyspneaEbola virusEmergency SituationEnrollmentEvolutionFDA Emergency Use AuthorizationFundingGeneral PopulationGenetic VariationGoalsGrantHaplotypesHospitalizationHospitalsIn VitroInfectionLeadMeasuresMediatingMedical RecordsMiddle East Respiratory Syndrome CoronavirusMonitorMonoclonal AntibodiesMutationNatureNucleotidesOligonucleotidesOutcomePatientsPersonsPneumoniaPolymerasePopulationPopulation DynamicsProbabilityProdrugsRNA VirusesRNA-Directed RNA PolymeraseRecording of previous eventsRecoveryReportingResearch PersonnelResistanceRespiratory distressRiskSARS coronavirusSamplingSeedsSeriesSpecimenSymptomsTestingTherapeuticTimeVariantViralViral Load resultVirusWorkbiobankdeep sequencingdesigngenome sequencingglobal healthin silicomimicrymolecular sequence databasemutantnasal swabnasopharyngeal swabnucleotide analogonline repositorypandemic diseasepathogenpatient populationpressureremdesivirresearch clinical testingresistance mutationrespiratory pathogenresponsesevere COVID-19therapeutic evaluationtreatment comparisontreatment strategyviral RNAviral resistancevirologywhole genome
项目摘要
PROJECT SUMMARY
The rapid spread of the SARS-CoV-2 pandemic around the globe has led to an urgent and ongoing evaluation
of therapeutic strategies for the treatment of Coronavirus Disease 2019 (COVID-19). While a handful of host-
directed therapies are being used for the treatment of severe disease, including monoclonal antibodies and
dexamethasone, there is only one antiviral with emergency use authorization, the nucleotide analog remdesivir
(GS-5734). Remdesivir is thought to inhibit the viral RNA-dependent RNA polymerase, Nsp12, through
nucleotide mimicry and early chain termination. As use of remdesivir for the treatment of COVID-19 escalates, it
is essential to understand the nature and risk of developing antiviral resistance. We hypothesize that intra-host
variation in Nsp12 could allow for the evolution of remdesivir resistance. In this exploratory grant, we propose to
test this hypothesis by quantifying the SARS-CoV-2 viral diversity that arises in hospitalized patients over time
with and without remdesivir treatment (Aim 1), and by determining the impact of known Nsp12 mutations on
polymerase activity and sensitivity to remdesivir (Aim 2). In Aim 1, we will leverage a biobank of longitudinally
collected nasopharyngeal swabs from hospitalized COVID-19 patients at Northwestern Memorial Hospital.
Specimens were collected every 4 days after enrollment for up to one month, including specimens from 8 patients
given remdesivir. We are continuing to collect specimens and intend to enroll an additional 50 COVID-19 patients
over the coming months. Deep, whole genome sequencing of SARS-CoV-2 viruses from each specimen will be
performed to classify the viral variants detected within each patient over time. The nature and extent of variation
will be compared by time point, viral load, and treatment course as determined from medical record data. These
studies will be complemented with deep sequencing of viruses produced ex vivo in the presence of varying
concentrations of remdesivir. Overall, this work will determine the nature and extent of SARS-CoV-2 intra-host
variation that develops in hospitalized patients and will determine the impact of remdesivir treatment on that
variation. In Aim 2, in vitro oligonucleotide extension assays will be used to assess the impact of previously
described Nsp12 mutations on polymerase activity and remdesivir efficacy. Documented mutations near the
remdesivir binding pocket and Nsp12 active site, newly documented haplotypes arising in our patient population,
and Nsp12 mutants found to be under selective pressure will be assessed first for polymerase activity followed
by remdesivir sensitivity. The phylodynamic histories of impactful mutations and haplotypes will be followed to
look for evidence of selection in the population. Together, these results will assess the risk of emergent
remdesivir resistance and additionally identify potential resistance mutations for active monitoring.
项目摘要
SARS-CoV-2大流行在地球仪的迅速蔓延导致了一项紧急和持续的评估
治疗2019冠状病毒病(COVID-19)的治疗策略。虽然有少数的主机-
定向疗法用于治疗严重疾病,包括单克隆抗体,
地塞米松,只有一种抗病毒药物获得紧急使用许可,即核苷酸类似物Remdesivir
(GS-5734)。Remdesivir被认为通过以下途径抑制病毒RNA依赖性RNA聚合酶Nsp 12,
核苷酸模拟和早期链终止。随着瑞德西韦用于治疗COVID-19的使用升级,
对于了解抗病毒药物耐药性的性质和风险至关重要。我们假设宿主内
Nsp 12的变异可能导致瑞德西韦耐药性的演变。在这一探索性赠款中,我们建议
通过量化住院患者随时间推移出现的SARS-CoV-2病毒多样性来验证这一假设
有和没有remdesivir治疗(目的1),并通过确定已知的Nsp 12突变对
聚合酶活性和对Remdesivir的敏感性(Aim 2)。在目标1中,我们将利用纵向生物样本库,
从西北纪念医院住院的COVID-19患者中收集鼻咽拭子。
入组后每4天采集一次标本,持续1个月,包括8例患者的标本
给予瑞姆西韦。我们正在继续收集标本,并打算再招募50名新冠肺炎患者
在接下来的几个月里。将对每个标本中的SARS-CoV-2病毒进行深入的全基因组测序,
对每个患者体内检测到的病毒变异进行分类。变异的性质和程度
将根据病历数据确定的时间点、病毒载量和疗程进行比较。这些
研究将通过在存在不同的DNA的情况下离体产生的病毒的深度测序来补充。
Remdesivir的浓度总体而言,这项工作将确定SARS-CoV-2宿主内的性质和程度
在住院患者中发生的变异,并将决定Remdesivir治疗对其的影响。
变化量在目标2中,将使用体外寡核苷酸延伸测定来评估先前的寡核苷酸延伸的影响。
描述了Nsp 12突变对聚合酶活性和Remdesivir功效的影响。记录显示,
Remdesivir结合口袋和Nsp 12活性位点,在我们的患者人群中出现的新记录的单倍型,
发现处于选择压力下的Nsp 12突变体将首先评估聚合酶活性,
通过Remdesivir敏感性。影响突变和单倍型的动态历史将被跟踪,
在种群中寻找选择的证据。总之,这些结果将评估紧急风险,
Remdesivir耐药性,并额外识别潜在的耐药突变以进行主动监测。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Overlapping Delta and Omicron Outbreaks During the COVID-19 Pandemic: Dynamic Panel Data Estimates.
- DOI:10.2196/37377
- 发表时间:2022-06-03
- 期刊:
- 影响因子:8.5
- 作者:Lundberg, Alexander L.;Lorenzo-Redondo, Ramon;Hultquist, Judd F.;Hawkins, Claudia A.;Ozer, Egon A.;Welch, Sarah B.;Prasad, P. V. Vara;Achenbach, Chad J.;White, Janine, I;Oehmke, James F.;Murphy, Robert L.;Havey, Robert J.;Post, Lori A.
- 通讯作者:Post, Lori A.
Has Omicron Changed the Evolution of the Pandemic?
- DOI:10.2196/35763
- 发表时间:2022-01-31
- 期刊:
- 影响因子:8.5
- 作者:Lundberg AL;Lorenzo-Redondo R;Ozer EA;Hawkins CA;Hultquist JF;Welch SB;Prasad PVV;Oehmke JF;Achenbach CJ;Murphy RL;White JI;Havey RJ;Post LA
- 通讯作者:Post LA
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Judd F Hultquist其他文献
Judd F Hultquist的其他文献
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{{ truncateString('Judd F Hultquist', 18)}}的其他基金
Exploring Small Molecule Inhibitors of PAF1C as Novel HIV Latency Reversal Agents
探索 PAF1C 小分子抑制剂作为新型 HIV 潜伏期逆转剂
- 批准号:
10762258 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Deciphering the Role of CPSF6 in HIV Infection
解读 CPSF6 在 HIV 感染中的作用
- 批准号:
10450049 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Deciphering the Role of CPSF6 in HIV Infection
解读 CPSF6 在 HIV 感染中的作用
- 批准号:
10646402 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Assessing the Risk of SARS-CoV-2 Remdesivir Resistance
评估 SARS-CoV-2 瑞德西韦耐药性风险
- 批准号:
10289055 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
Deciphering the Role of CPSF6 in HIV Infection
解读 CPSF6 在 HIV 感染中的作用
- 批准号:
10327094 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
The Influence of Early Integration Events on HIV Latency and Reactivation Potential
早期整合事件对 HIV 潜伏期和再激活潜力的影响
- 批准号:
9750620 - 财政年份:2018
- 资助金额:
$ 20万 - 项目类别:
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