Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound
确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献
基本信息
- 批准号:10460575
- 负责人:
- 金额:$ 78.67万
- 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 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AchievementAcquired Immunodeficiency SyndromeAddressAdherenceAgeAnatomyAutopsyBiological MarkersBloodBrainCCR5 geneCD4 Positive T LymphocytesCXCR4 geneCell physiologyCellsClinical TrialsCollectionControlled StudyCuesDNADataDevelopmentDisease ProgressionDisease remissionEnrollmentEquilibriumFingerprintGenetic FingerprintingsGoalsHIVHIV InfectionsIn VitroIndividualInfectionInflammationInterruptionInterventionKineticsLocationLongevityMacaca mulattaMediatingModelingNatureNeuraxisNeuropathogenesisPersonsPhagocytosisPrimatesRecording of previous eventsRegimenResearchResearch PersonnelResidual stateResistanceRestRoleSIVSpecimenT-Cell DepletionTimeTissuesVariantViralViral GenomeViral Load resultViral reservoirVirionVirusVirus LatencyVirus ReplicationWorkanimal resourceantiretroviral therapybrain tissueclinically relevantcostdesigndetection limitin vivoinsightmacrophagememory CD4 T lymphocytemultidisciplinarynovelnovel strategiesnovel therapeutic interventionpeerside effectsocial stigmasuccesssynergismviral DNAviral RNAviral rebound
项目摘要
Abstract
Despite its success at suppressing viral loads, antiretroviral therapy (ART) cannot eradicate HIV infection. The
main obstacle to curing HIV infection is the ability of the virus to persist under suppressive ART in reservoirs of
latently infected cells, which are established early after infection and supports rebound to pre-treatment levels
if ART is interrupted. Despite the extraordinary challenge of persistent virus reservoirs, a few cases have
recently proved that prolonged viral remission after analytical therapy interruption (ATI) is possible.
Unfortunately, the specific mechanisms regulating HIV rebound remain very poorly understood, thus critically
limiting the development of novel therapeutic strategies aimed at eradication or remission of HIV infection. In
this project, we have assembled a multidisciplinary team of investigators to address directly in vivo how the
size and relative distribution of the reservoir in CD4 T cells and macrophages govern (i) the anatomic
location of persistent viral reservoirs; (ii) the exent of residual inflammation and neuropathogenesis;
and (iii) the time and extent of viral rebound after ATI. Specifically, we propose to alter directly in vivo and
in a highly relevant model for HIV infection (i.e., the SIV infection of rhesus macaques; RMs) the overall size of
virus reservoirs and its distribution between CD4 T cells and macrophages. These goals will be achieved (i) by
using the well-established model of ART-treated, SIV-infected RMs; (ii) by using a SIV swarm that allows
tracking of multiple viral variants; and (iii) by performing in vivo Ab-mediated CD4 T cell depletion before SIV
infection and after SIV-infection during suppressive ART. We will determine how the planned in vivo depleting
interventions alter the distribution of viral reservoirs between CD4 T cells and macrophages; impact the
kinetics and extent of viral rebound following ATI; and influence the cellular nature and genetic fingerprinting of
the rebounding virus. Finally, we will investigate the mechanisms favoring SIV infection and persistence in
macrophages when CD4 T cells are depleted.
We believe that the complementary, comprehensive, highly synergistic, and rigourosly controlled studies that
we propose will provide unprecedented, novel insights into (i) understanding how the cellular nature of the viral
reservoir regulate residual inflammation and viral persistence on ART and viral rebound after ATI, and (2) the
direct role of macrophages in harboring replication competent virus during long-term ART and contributing to
viral rebound after ATI. Critical for our aims, the SIV/RM model allows for investigating the CD4 T cells versus
macrophages contribution to viral reservoir not only in blood, but also in a large number of tissues collected
longitudinally and at necropsy, including CSF and brain tissues. These achievements will inform efforts to
design novel therapeutic strategies aimed at achieving prolonged viral remission of HIV infection.
摘要
尽管抗逆转录病毒疗法(ART)在抑制病毒载量方面取得了成功,但它不能根除艾滋病毒感染。的
治愈HIV感染的主要障碍是病毒在抑制性ART下在以下宿主中持续存在的能力:
潜伏感染的细胞,在感染后早期建立,并支持反弹至治疗前水平
如果ART中断。尽管持续性病毒储库的挑战非常大,但少数病例
最近证明,分析治疗中断(ATI)后延长病毒缓解是可能的。
不幸的是,调节HIV反弹的具体机制仍然知之甚少,因此至关重要。
限制了旨在根除或缓解HIV感染的新治疗策略的发展。在
在这个项目中,我们组建了一个多学科的研究小组,直接在体内解决如何在体内,
CD 4 T细胞和巨噬细胞中储库的大小和相对分布决定(i)解剖结构
持久性病毒库的位置;(ii)残余炎症和神经发病机制的存在;
和(iii)ATI后病毒反弹的时间和程度。具体来说,我们建议直接在体内改变,
在HIV感染的高度相关模型中(即,恒河猴的SIV感染; RM)的总体大小
病毒库及其在CD 4 T细胞和巨噬细胞之间的分布。这些目标将通过以下方式实现:(i)
使用ART治疗,SIV感染RM的成熟模型;(ii)通过使用SIV群,
追踪多种病毒变体;和(iii)通过在SIV前进行体内Ab介导的CD 4 T细胞耗竭
感染和SIV感染后,在抑制性ART。我们将确定如何计划在体内消耗
干预措施改变了CD 4 T细胞和巨噬细胞之间病毒储库的分布;
ATI后病毒反弹的动力学和程度;并影响
反弹病毒最后,我们将研究有利于SIV感染和持续存在的机制。
当CD 4 T细胞耗尽时,巨噬细胞被吞噬。
我们认为,互补的,全面的,高度协同的,严格控制的研究,
我们的建议将提供前所未有的,新的见解(i)了解如何细胞性质的病毒,
储库调节ART时的残余炎症和病毒持续存在以及ATI后的病毒反弹,以及(2)
在长期ART期间,巨噬细胞在携带有复制能力的病毒中的直接作用,
ATI后病毒反弹对于我们的目标至关重要的是,SIV/RM模型允许研究CD 4 T细胞与
巨噬细胞不仅在血液中,而且在收集的大量组织中对病毒储库起作用
纵向和尸检时,包括CSF和脑组织。这些成就将为以下努力提供信息:
设计新的治疗策略,旨在实现延长HIV感染的病毒缓解。
项目成果
期刊论文数量(0)
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{{ truncateString('JACOB D ESTES', 18)}}的其他基金
Selection and Evolution of HIV-1 reservoir cells in blood and tissues
血液和组织中 HIV-1 储存细胞的选择和进化
- 批准号:
10176754 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound
确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献
- 批准号:
10673779 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Selection and Evolution of HIV-1 reservoir cells in blood and tissues
血液和组织中 HIV-1 储存细胞的选择和进化
- 批准号:
10465135 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound
确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献
- 批准号:
10082887 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Selection and Evolution of HIV-1 reservoir cells in blood and tissues
血液和组织中 HIV-1 储存细胞的选择和进化
- 批准号:
10269039 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Determining the relative contribution of CD4 T cells and macrophages to HIV persistence and rebound
确定 CD4 T 细胞和巨噬细胞对 HIV 持续存在和反弹的相对贡献
- 批准号:
10251333 - 财政年份:2020
- 资助金额:
$ 78.67万 - 项目类别:
Novel ISH Approaches to Quantify Replication Competent Reservoirs
量化复制能力储库的新 ISH 方法
- 批准号:
10413135 - 财政年份:2019
- 资助金额:
$ 78.67万 - 项目类别:
Novel ISH Approaches to Quantify Replication Competent Reservoirs
量化复制能力储库的新 ISH 方法
- 批准号:
10164715 - 财政年份:2019
- 资助金额:
$ 78.67万 - 项目类别:
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