Early intervention with anti-proliferative therapy close to ART initiation to limit long-term SIV persistence
在 ART 开始时进行早期抗增殖治疗干预,以限制 SIV 的长期持续存在
基本信息
- 批准号:10849960
- 负责人:
- 金额:$ 90.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAcuteAnimal ModelAnimalsAntigensAutologousBindingBlood specimenCD28 geneCD3 AntigensCD4 Positive T LymphocytesCell Culture TechniquesCell ProliferationCellsClonalityClone CellsCombined Modality TherapyDNADasatinibDeuteriumDeuterium OxideDoseDrug CombinationsDrug ScreeningEarly InterventionFDA approvedHIVHIV InfectionsHIV-1Half-LifeHumanIL7 geneImmune responseImmune systemImmunologic MemoryImmunosuppressionIndividualInfectionInterruptionLabelLibrariesLymphocyteLymphopeniaMacacaMacaca mulattaMeasuresMolecularMonitorOrganPeripheral Blood Mononuclear CellPersonsPharmaceutical PreparationsPlasmaPlayPopulationPrimary InfectionProliferatingProvirusesRecoveryRegimenReportingRoleSIVSafetySerumSourceStructureT-Cell DepletionT-Cell ProliferationT-Lymphocyte SubsetsTestingTherapeuticTherapeutic EffectThymidine KinaseTimeTissuesToxic effectViralViral ProteinsVirusVirus DiseasesWaterantiproliferative agentsantiretroviral therapychemotherapeutic agentimmunoregulationin vitro testingin vivointegration sitekinase inhibitorleukemiamathematical modelmycophenolate mofetilpharmacodynamic modelpharmacokinetic modelpharmacokinetics and pharmacodynamicspharmacologicpre-clinicalresponsetargeted agentviral rebound
项目摘要
PROJECT 1 SUMMARY
HIV persists despite decades of antiretroviral therapy (ART) because of a population of latently infected CD4+
T cells known as the HIV reservoir. The HIV reservoir is sustained by proliferation of infected CD4+ T cells, which
do not express enough viral protein to be eliminated by HIV-specific immune responses. While proliferation of
cells is a promising target for curing HIV and eliminating the need for lifelong ART, a comprehensive preclinical
structure to develop a lymphocyte anti-proliferation therapeutic strategy does not exist.
Recent evidence suggests that CD4+ T cell proliferation plays a vital role in generating multiple proliferative
clones of latently infected cells extremely early during untreated HIV infection. We developed a mathematical
model which suggests that massive CD4+ T cell proliferation coincident with recovery from CD4+ lymphopenia,
occurs during weeks 1-4 of primary HIV infection and is vital for generating much of the HIV reservoir. We
hypothesize that effective anti-proliferative (AP) therapy given during this critical three-week window will limit the
volume and alter the clonal structure of the HIV reservoir.
In Aim 1 of this application, Dr. Adam Spivak will test small molecular agents targeting CD4+ T cell
proliferation given alone and in combination. A comprehensive library of immunomodulatory and
chemotherapeutic agents with high therapeutic potential will be tested for their AP effects ex vivo on CD4+ T cell
cultures, ex vivo on latently HIV-1 infected cells derived from human donors, and in vivo in uninfected rhesus
macaques by measuring impact on CD4+ T cell turnover using deuterium water labeling. Finally, Dr. Joshua
Schiffer will utilize mathematical models which capture drug pharmacokinetics and pharmacodynamics, as well
as the underlying dynamics of CD4+ T cell subsets within the HIV reservoir, to optimize selection of single drug
or combination anti-proliferative (AP) regimens for dosing of SIV infected animals in Aim 2.
In Aim 2, Dr. Joseph Mudd will evaluate the effects of optimized AP agents on early reservoir formation
dynamics in 24 SIV-infected rhesus macaques: 6 will receive ART alone between weeks 1-25 post infection; 6
will receive ART alone between weeks 4-28 post infection; 6 will receive ART between weeks 1-25 and optimized
AP therapy between weeks 1-4 post infection; 6 will receive ART between weeks 4-28 and optimized AP therapy
between weeks 1-4 post infection. Optimized AP regimens will be selected from Aim 1.
During ART, we will measure the in vivo AP therapeutic effect on 1) SIV reservoir volume with total and
intact SIV DNA, 2) reservoir CD4+ T cell subset composition, 3) in vivo CD4+ T cell turnover with D2O labeling,
and 4) SIV reservoir clonal structure using integration site sequencing, based on frequent longitudinal sampling
of blood and gut tissues. After 24 weeks of ART, we will stop ART and monitor viral rebound for up to 4 months.
We hypothesize that AP therapy between weeks 1 and 4 post infection will reduce total and intact SIV DNA and
decrease reservoir clonality following 6 months of ART, and increase time to SIV rebound after ART interruption.
项目1概要
尽管抗逆转录病毒治疗(ART)数十年,艾滋病毒仍然存在,因为潜伏感染的CD 4 +
T细胞被称为艾滋病病毒的储存库。HIV病毒库通过受感染的CD 4 + T细胞的增殖来维持,
不表达足够的病毒蛋白以被HIV特异性免疫反应消除。虽然扩散的
细胞是治愈艾滋病毒和消除终身ART的需要的一个有前途的目标,一个全面的临床前
不存在开发淋巴细胞抗增殖治疗策略的结构。
最近的证据表明,CD 4 + T细胞增殖在产生多种增殖性T细胞中起着至关重要的作用。
在未经治疗的HIV感染期间,潜伏感染细胞的克隆非常早。我们开发了一个数学模型
该模型表明大量的CD 4 + T细胞增殖与从CD 4+淋巴细胞减少症的恢复一致,
发生在原发性HIV感染的第1-4周,对于产生大部分HIV库至关重要。我们
假设在这关键的三周窗口期内给予有效的抗增殖(AP)治疗将限制
改变HIV库的克隆结构。
在本申请的目标1中,Adam Spivak博士将测试靶向CD 4 + T细胞的小分子药物。
单独和组合给予的增殖。一个全面的免疫调节和
将测试具有高治疗潜力的化学治疗剂对CD 4 + T细胞的离体AP作用
培养物,在来自人供体的潜伏HIV-1感染细胞上离体培养,以及在未感染恒河猴中体内培养
猕猴通过使用氘水标记测量对CD 4 + T细胞周转的影响。最后,约书亚博士
希弗将利用数学模型,捕捉药物的药代动力学和药效学,以及
作为HIV库内CD 4 + T细胞亚群的潜在动力学,以优化单一药物的选择
或组合抗增殖(AP)方案用于目标2中SIV感染动物的给药。
在目标2中,Joseph Mudd博士将评估优化的AP试剂对早期储层形成的影响
在24只SIV感染的恒河猴中的动态:6只将在感染后1-25周之间单独接受ART; 6只
将在感染后第4-28周之间单独接受ART; 6名将在第1-25周之间接受ART并优化
感染后第1-4周接受AP治疗; 6例将在第4-28周接受ART和优化AP治疗
感染后1-4周。将从目标1中选择优化的AP方案。
在ART期间,我们将测量体内AP对1)SIV储库体积的治疗效果,
完整的SIV DNA,2)储库CD 4 + T细胞亚群组成,3)D2 O标记的体内CD 4 + T细胞更新,
和4)基于频繁纵向采样的使用整合位点测序的SIV储库克隆结构
血液和肠道组织ART治疗24周后,我们将停止ART治疗,并监测病毒反弹长达4个月。
我们假设感染后1 - 4周的AP治疗会减少总的和完整的SIV DNA,
在ART治疗6个月后,降低储层的克隆性,并增加ART中断后SIV反弹的时间。
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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Joseph Christopher Mudd其他文献
Joseph Christopher Mudd的其他文献
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{{ truncateString('Joseph Christopher Mudd', 18)}}的其他基金
The intersection of diet, cell metabolic state, and SIV reservoir transcription
饮食、细胞代谢状态和 SIV 储存库转录的交叉点
- 批准号:
10618546 - 财政年份:2023
- 资助金额:
$ 90.9万 - 项目类别:
Role of RhCMV in shaping the SIV proviral landscape
RhCMV 在塑造 SIV 前病毒景观中的作用
- 批准号:
10541869 - 财政年份:2022
- 资助金额:
$ 90.9万 - 项目类别:
Role of RhCMV in shaping the SIV proviral landscape
RhCMV 在塑造 SIV 前病毒景观中的作用
- 批准号:
10397879 - 财政年份:2022
- 资助金额:
$ 90.9万 - 项目类别:
Mechanisms and Therapeutic Targeting of CD4 Down regulation in African Green Monkeys
非洲绿猴 CD4 下调的机制和治疗目标
- 批准号:
10378164 - 财政年份:2021
- 资助金额:
$ 90.9万 - 项目类别:
Mechanisms and Therapeutic Targeting of CD4 Down regulation in African Green Monkeys
非洲绿猴 CD4 下调的机制和治疗目标
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10254703 - 财政年份:2021
- 资助金额:
$ 90.9万 - 项目类别:
Innate Lymphoid Cell Loss in HIV-1 and SIV Infection
HIV-1 和 SIV 感染中的先天淋巴细胞损失
- 批准号:
9618331 - 财政年份:2020
- 资助金额:
$ 90.9万 - 项目类别:
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