Exploiting Highly Networked CTL Epitopes to Achieve a Functional HIV Cure
利用高度网络化的 CTL 表位实现功能性 HIV 治愈
基本信息
- 批准号:10751795
- 负责人:
- 金额:$ 18.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Adoptive TransferAlgorithmsAllelesAnatomyAreaBloodCD4 Positive T LymphocytesCell SeparationCellsChronicClone CellsCoculture TechniquesCollaborationsCore FacilityCytolysisCytotoxic T-LymphocytesDNADataDrug resistanceDrug toxicityEffectivenessEpidemicEpitopesFellowshipGoalsHIVHIV vaccineHIV/AIDSImpairmentIndividualInvestigationInvestmentsKnowledgeLifeLinkMediatingMedicalMethodologyMissionModalityMutagenesisMutateMutationPathway AnalysisPatientsPharmaceutical PreparationsPostdoctoral FellowProgressive DiseaseProteomePublic HealthPublishingResearchResourcesRestScienceSiteStructureT cell responseT-Lymphocyte EpitopesTherapeuticTissue SampleTissuesUnited States National Institutes of HealthVaccine DesignVaccinesViralViral reservoirVirusVirus LatencyVirus ReplicationWorkantiretroviral therapydeep sequencingdesigneconomic implicationgastrointestinalhumanized mousein vivoinnovationlatent HIV reservoirmouse modelnovelnovel strategiesnovel therapeuticsperipheral bloodpreventprotein structurerational designresistance mutationresponsetheoriestherapeutic vaccinetherapeutically effectiveviral rebound
项目摘要
ABSTRACT
The HIV/AIDS epidemic continues to have enormous medical, societal and economic implications worldwide.
While combination anti-retroviral therapy (cART) has greatly reduced the global burden of HIV, the ability of the
virus to establish a persistent reservoir within the body requires that HIV-infected individuals remain on lifelong
treatment. As a result, new modalities that can suppress the viral reservoir and thereby limit the requirement of
HIV treatment are greatly needed. Recent efforts have been focused on the induction of cytotoxic T cells
(CTLs) by therapeutic vaccines. However, the accumulation of CTL escape mutations in chronically infected,
cART-suppressed patients has greatly limited the ability of CTLs to successfully prevent viral rebound following
cART cessation. Thus, in order to counteract this viral escape, this DP2 proposal will focus on the study of CTL
responses to a new set of targets, known as `highly networked' epitopes, to determine whether they can form
the basis of a novel therapeutic CTL-based vaccine for HIV. These highly networked epitopes were identified
using an innovative approach known as structure-based network analysis. By applying network theory
principles to HIV protein structure data, the approach was able to identify a set of epitopes that are intolerant to
mutation, but which are also presented by a broad array of HLA alleles. Moreover, the targeting of highly
networked epitopes by functional CTL responses was shown to strongly distinguish individuals who naturally
control HIV from those with progressive disease. Thus, the goal now is to determine whether CTLs directed
against highly networked epitopes can also suppress viral outgrowth following cART cessation in the remaining
~99% of chronically-infected, cART-treated individuals. This will be accomplished by: (i) deep sequencing
highly networked epitopes in proviral DNA derived from peripheral blood and gastrointestinal tissue and (ii)
determining whether CTLs targeting highly networked epitopes can suppress latent virus outgrowth both ex
vivo and in a humanized mouse model. Demonstrating the effectiveness of CTL-mediated responses to highly
networked epitopes will confirm the value of the structure-based network analysis approach to guide the
rational design of a effective, therapeutic CTL-based vaccine for HIV.
抽象的
艾滋病毒/艾滋病流行在全球范围内仍然具有巨大的医学,社会和经济影响。
虽然抗逆转录病毒疗法(CART)大大减轻了全球艾滋病毒负担,但
在体内建立持续的水库的病毒需要艾滋病毒感染的人留在终生上
治疗。结果,可以抑制病毒库的新方式,从而限制了
非常需要艾滋病毒治疗。最近的努力集中在诱导细胞毒性T细胞上
(CTL)通过治疗疫苗。但是,CTL逃脱突变在长期感染中的积累,
被塞车的患者极大地限制了CTL成功防止病毒反弹的能力
推车戒烟。因此,为了抵消这种病毒逃生,该DP2提案将集中于CTL的研究
对一组新目标的响应,称为“高度网络”表位,以确定它们是否可以形成
基于CTL的新型艾滋病毒疫苗的基础。确定了这些高度网络的表位
使用称为基于结构网络分析的创新方法。通过应用网络理论
HIV蛋白结构数据的原理,该方法能够识别一组不宽容的表位
突变,但也由各种HLA等位基因呈现。此外,高度定位
通过功能CTL响应的网络表位显示出强烈区分自然的人
从患有进行性疾病的患者控制艾滋病毒。因此,现在的目标是确定CTL是否指向
在剩余
〜99%的慢性感染,手推车处理的个体。这将通过:(i)深入测序
源自周围血液和胃肠道组织的前病毒DNA的高度网络表位,(ii)
确定针对高度网络表位的CTL是否可以抑制潜在病毒的生长
体内和人源化的小鼠模型。证明CTL介导的对高度响应的有效性
网络表位将确认基于结构的网络分析方法的价值,以指导
有效的,基于CTL的艾滋病毒疫苗的合理设计。
项目成果
期刊论文数量(1)
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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Gaurav Das Gaiha其他文献
Gaurav Das Gaiha的其他文献
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{{ truncateString('Gaurav Das Gaiha', 18)}}的其他基金
Investigating the Protective Efficacy of SIV/HIV T and B cell Immunity Induced by RNA Replicons
研究 RNA 复制子诱导的 SIV/HIV T 和 B 细胞免疫的保护功效
- 批准号:
10673223 - 财政年份:2023
- 资助金额:
$ 18.05万 - 项目类别:
Harnessing Highly Networked HLA-E-Restricted CTL Epitopes to Achieve a Broadly Effective HIV Cure
利用高度网络化的 HLA-E 限制性 CTL 表位实现广泛有效的 HIV 治愈
- 批准号:
10684371 - 财政年份:2023
- 资助金额:
$ 18.05万 - 项目类别:
Exploiting Highly Networked CTL Epitopes to Achieve a Functional HIV Cure
利用高度网络化的 CTL 表位实现功能性 HIV 治愈
- 批准号:
10475751 - 财政年份:2020
- 资助金额:
$ 18.05万 - 项目类别:
Exploiting Highly Networked CTL Epitopes to Achieve a Functional HIV Cure
利用高度网络化的 CTL 表位实现功能性 HIV 治愈
- 批准号:
10687039 - 财政年份:2020
- 资助金额:
$ 18.05万 - 项目类别:
Exploiting Highly Networked CTL Epitopes to Achieve a Functional HIV Cure
利用高度网络化的 CTL 表位实现功能性 HIV 治愈
- 批准号:
10246309 - 财政年份:2020
- 资助金额:
$ 18.05万 - 项目类别:
Leveraging CTLs targeting highly networked epitopes to suppress the latent HIV-1 reservoir
利用针对高度网络化表位的 CTL 来抑制潜在的 HIV-1 病毒库
- 批准号:
9906843 - 财政年份:2019
- 资助金额:
$ 18.05万 - 项目类别:
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