Immunological Strategies to Modulate SIV Rebound Following ART Interruption
ART 中断后调节 SIV 反弹的免疫策略
基本信息
- 批准号:10224003
- 负责人:
- 金额:$ 149.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAcquired Immunodeficiency SyndromeAddressAnti-Retroviral AgentsAntibody TherapyArchivesBar CodesBinding SitesBone MarrowCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCellsCellular ImmunityEquilibriumEventExcisionGrowthHIVHIV InfectionsHelper-Inducer T-LymphocyteHumoral ImmunitiesImmune responseImmunityImmunologicsImmunologyImmunotherapyIndividualInfectionInterruptionKineticsLocationLymphocyteLymphoidLymphoid TissueMacaca mulattaMathematicsMeasuresModelingPlasmaProcessRNA InterferenceReagentRecrudescencesReportingRestSIVSourceSpleenStochastic ProcessesT cell responseTherapeuticTimeTissuesTonsilViralViral Load resultViremiaVirusantiretroviral therapybasecell typedesignexperiencehuman pathogenimmunological interventionimprovedin vivoinnovationinsightlatent HIV reservoirlymph nodesmathematical modelneutralizing antibodynonhuman primatenovelpassive antibodiespreventprogrammed cell death protein 1programssimian human immunodeficiency virustherapeutic evaluationviral fitnessviral reboundvirology
项目摘要
Abstract. The majority of antiretroviral (ART) treated HIV-infected individuals experience detectable rebound
in HIV plasma viremia within weeks following interruption of ART. The kinetics of rebound virus reactivation are
a correlate of the size of the archived reservoir and a key measure of reductions therein. Recent mathematical
estimates suggest that virus reactivation events occur every 5-8 days following ART removal. Immunologic
strategies to prevent or extend the time to virus reactivation and HIV rebound are critically needed to enable
durable control or eradication of HIV within infected individuals. Rebounding plasma virus following ART
interruption is thought to primarily originate from long-lived resting CD4+ T cell reservoirs, largely PD-1+ T
follicular helper cells, within secondary lymphoid tissue (LT) such as lymph nodes, spleen, tonsil, bone marrow,
and lymphoid aggregates within gut tissue. This P01 proposal will explore and model two immunologic
strategies to prevent, limit, or delay viral rebound by (1) directly targeting rebounding virus through passive nAb
therapy in transmitted founder-SHIV infected rhesus macaques (K. Bar/G. Shaw, Project 1) and (2) inhibiting
lymphocyte egress from LT to both prevent infected CD4+ T cell redistribution and enable the interaction
between reactivated infected CD4+ T cells and protective CD8+ T cells in lymphoid tissue after ART
interruption in SIV infected rhesus macaques (M. Betts, Project 2). Importantly, we will employ bar-coded SIV
and SHIV viruses in both projects (B. Keele), allowing us to precisely track reactivation rate at a clonal level,
and to discern potential tissue and cell types of viral reactivation. These projects will be supported by experts in
mathematical modeling (M. Davenport, Analysis and Modeling Core) and nonhuman primate studies (M.
Paiardini/G. Silvestri Non-Human Primate Core). Together these studies will provide novel insights into
immunological strategies to delay or prevent viral rebound after ART interruption.
PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
抽象的。大多数接受抗逆转录病毒(ART)治疗的艾滋病毒感染者经历了可检测到的反弹。
在抗逆转录病毒疗法中断后的几周内出现艾滋病毒血浆病毒血症。反跳病毒重新激活的动力学为
存档的水库大小的相关性和其中减少的关键措施。最新数学
据估计,病毒重新激活事件在ART移除后每5-8天发生一次。免疫学
预防或延长病毒重新激活和艾滋病毒反弹的时间的战略至关重要,以实现
持久控制或根除感染者体内的艾滋病毒。抗逆转录病毒治疗后血浆病毒反弹
中断被认为主要源于长期静息的CD4+T细胞库,主要是PD-1+T细胞
滤泡辅助细胞,位于次级淋巴组织(LT)内,如淋巴结、脾、扁桃体、骨髓、
和肠道组织内的淋巴集合体。这项P01提案将探索和模拟两种免疫学
通过以下方式防止、限制或延迟病毒反弹的策略:(1)通过被动NAB直接靶向反弹病毒
方正-希氏病毒感染恒河猴的治疗(K.Bar/G.Shaw,项目1)和(2)抑制
淋巴细胞从LT流出,既防止感染的CD4+T细胞重新分布,又使相互作用成为可能
ART术后淋巴组织中再激活感染的CD4+T细胞与保护性CD8+T细胞的比较
阻断感染SIV的恒河猴(M.Betts,项目2)。重要的是,我们将使用条形码SIV
和两个项目中的SHIV病毒(B.Keele),使我们能够在克隆水平上精确跟踪重新激活率,
并识别病毒重新激活的潜在组织和细胞类型。这些项目将得到以下领域专家的支持
数学建模(M.Davenport,分析和建模核心)和非人灵长类研究(M.
Paiardini/G.Silvestri非人类灵长类核心)。总而言之,这些研究将为
延缓或防止ART阻断后病毒反弹的免疫策略。
PHS 398/2590(06/09版)页面续格式页面
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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Katharine June Bar其他文献
Katharine June Bar的其他文献
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{{ truncateString('Katharine June Bar', 18)}}的其他基金
Determining the effects of broadly neutralizing antibodies at antiretroviral therapy initiation
确定广泛中和抗体在抗逆转录病毒治疗开始时的作用
- 批准号:
10772448 - 财政年份:2023
- 资助金额:
$ 149.74万 - 项目类别:
Complementing broadly neutralizing antibodies and autologous responses to restrict virus escape and durably suppress HIV-1
补充广泛中和抗体和自体反应,以限制病毒逃逸并持久抑制 HIV-1
- 批准号:
10469169 - 财政年份:2022
- 资助金额:
$ 149.74万 - 项目类别:
Complementing broadly neutralizing antibodies and autologous responses to restrict virus escape and durably suppress HIV-1
补充广泛中和抗体和自体反应,以限制病毒逃逸并持久抑制 HIV-1
- 批准号:
10608215 - 财政年份:2022
- 资助金额:
$ 149.74万 - 项目类别:
Characterizing the viral and host effector mechanisms that govern HIV-1 rebound
表征控制 HIV-1 反弹的病毒和宿主效应机制
- 批准号:
10629260 - 财政年份:2021
- 资助金额:
$ 149.74万 - 项目类别:
Characterizing the viral and host effector mechanisms that govern HIV-1 rebound
表征控制 HIV-1 反弹的病毒和宿主效应机制
- 批准号:
10437036 - 财政年份:2021
- 资助金额:
$ 149.74万 - 项目类别:
Novel macrophage-tropic transmitted/founder SHIV model of CNS persistence to evaluate CRISPR/Cas9 gene editing
用于评估 CRISPR/Cas9 基因编辑的新型巨噬细胞嗜性传播/中枢神经系统持久性 SHIV 模型
- 批准号:
10331568 - 财政年份:2021
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$ 149.74万 - 项目类别:
Novel macrophage-tropic transmitted/founder SHIV model of CNS persistence to evaluate CRISPR/Cas9 gene editing
用于评估 CRISPR/Cas9 基因编辑的新型巨噬细胞嗜性传播/中枢神经系统持久性 SHIV 模型
- 批准号:
10443900 - 财政年份:2021
- 资助金额:
$ 149.74万 - 项目类别:
Novel macrophage-tropic transmitted/founder SHIV model of CNS persistence to evaluate CRISPR/Cas9 gene editing
用于评估 CRISPR/Cas9 基因编辑的新型巨噬细胞嗜性传播/中枢神经系统持久性 SHIV 模型
- 批准号:
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$ 149.74万 - 项目类别:
Characterizing the viral and host effector mechanisms that govern HIV-1 rebound
表征控制 HIV-1 反弹的病毒和宿主效应机制
- 批准号:
10332623 - 财政年份:2021
- 资助金额:
$ 149.74万 - 项目类别:
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