A Pilot Clinical Trial for HIV-1 Eradication
根除 HIV-1 的试点临床试验
基本信息
- 批准号:8892586
- 负责人:
- 金额:$ 190.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-02-15 至 2016-01-31
- 项目状态:已结题
- 来源:
- 关键词:Anti-Retroviral AgentsBiological AssayCD4 Positive T LymphocytesCD8B1 geneCellsCessation of lifeChargeChronicClinicalClinical PharmacologyClinical TrialsCollaborationsCombined Modality TherapyConduct Clinical TrialsCytometryDNADataDendritic CellsDetectionDevelopmentDisease remissionEffector CellFrequenciesGene ExpressionGene Expression ProfilingGenesGenetic TranscriptionGoalsHIVHIV-1Histone Deacetylase InhibitorHumanHuman bodyImmuneImmune responseImmunologyInfectionInterferon-alphaInterferonsInterruptionInterventionKineticsLeadLifeMass Spectrum AnalysisMeasuresMediatingMonitorMyelogenousNatural ImmunityNatural Killer CellsOutcomeParticipantPatient CarePatientsPatternPharmaceutical PreparationsPharmacologic SubstancePlasmaProtocols documentationRNARandomizedResearch PersonnelSafetyT-LymphocyteT-Lymphocyte SubsetsTestingTimeTreatment ProtocolsViralWorkantiretroviral therapybasedesignimmune activationin vivointerdisciplinary collaborationmemory CD4 T lymphocytenovelnovel strategiespublic health relevancevirology
项目摘要
DESCRIPTION (provided by applicant): Although HIV-1 replication can be effectively suppressed with currently existing antiretroviral drugs, infection with HIV-1 remains incurable. This is primarily related to the ability of HIV-1 to establish a latent reservoir of HIV-1-infected
CD4 T cells that is unresponsive to currently available antiretroviral agents. Pharmacological reactivation of active HIV-1 gene expression in latently infected cells can result in cellular deat due to cytopathic effects or immune mediated clearance, and represents one of the most promising and most clinically advanced strategies to target latently infected cells. Results from prior pilot clinical trials, conducted in collaboration with the applicants, demonstrate that the potent histone deacetylase inhibitor (HDACi) panobinostat is effective in reversing HIV-1 latency and transiently increasing plasma HIV-1 RNA in vivo. In addition, this work indicated that viral reactivation with panobinostat resulted in a 3-4 fold reduction of CD4 T cell-associated HIV-1 DNA in a subset of patients, and that this decrease was associated with delayed viral rebound kinetics during an analytical treatment interruption. Interestingly, a detailed analysis of immune parameters revealed that decrease of HIV-1 DNA during panobinostat treatment was unrelated to the magnitude or breadth of HIV-1-specific CD8 T cells, but instead strongly correlated to the proportion of activated innate effector cells, such as NK cells and plasmacytoid dendritic cells. Together, these data suggest that HDACi can be used effectively as latency-reversing agents, and that innate effector cell immune responses are critical for reducing the reservoir of latently infected cells when viral reactivation is pharmacologically induced. This project sets out to integrate these observations into a conceptually novel HIV- 1 eradication strategy that is based on treatment with panobinostat as a latency-reversing agent in combination with pegylated IFNa-2a as an innate immune activator. We hypothesize that the concomitant use of both agents leads to innate immunity-dependent elimination of latently infected cells in which viral reactivation is pharmacologically induced. Specific aim (SA) 1 will focus on conducting a pilot clinical trial in which n=30 ART-treated HIV-1 patients will be randomized 2:1 to treatment with panobinostat and PEG-IFNa-2a during four one-week cycles, each of them separated by a three-week observation period, or to four cycles of treatment with panobinostat alone. In SA 2, we will investigate how the combined treatment regimen influences CD4 T cell-associated HIV-1 RNA, plasma RNA, HIV-1 DNA levels and the frequency of cells harboring replication-competent HIV-1. SA 3 is designed to comprehensively analyze immune effects associated with decreases in viral reservoir size, using a novel high-throughput mass spectrometry approach in combination with gene expression profiling and functional assays. This study represents an interdisciplinary collaboration of investigators with complementary expertise in HIV-1 virology, immunology, pharmacology and clinical patient care, and will be highly informative for the development of clinical strategies aiming at HIV-1 eradication.
描述(由申请人提供):尽管现有的抗逆转录病毒药物可以有效抑制HIV-1复制,但HIV-1感染仍然无法治愈。这主要与HIV-1建立HIV-1感染者的潜伏储库的能力有关。
CD 4 T细胞对目前可用的抗逆转录病毒药物无反应。潜伏感染细胞中活性HIV-1基因表达的药理学再激活可导致细胞死亡,这是由于细胞病变效应或免疫介导的清除,代表了靶向潜伏感染细胞的最有前途和临床上最先进的策略之一。与申请人合作进行的先前试点临床试验的结果表明,有效的组蛋白脱乙酰酶抑制剂(HDACi)帕比司他可有效逆转HIV-1潜伏期并瞬时增加体内血浆HIV-1 RNA。此外,这项工作表明,帕比司他的病毒再活化导致患者亚组中CD 4 T细胞相关HIV-1 DNA减少3-4倍,并且这种减少与分析治疗中断期间延迟的病毒反弹动力学相关。有趣的是,免疫参数的详细分析显示,帕比司他治疗期间HIV-1 DNA的减少与HIV-1特异性CD 8 T细胞的大小或宽度无关,而是与活化的先天效应细胞(如NK细胞和浆细胞样树突细胞)的比例密切相关。总之,这些数据表明,HDACi可以有效地用作潜伏期逆转剂,并且当病毒再活化被病毒诱导时,先天效应细胞免疫应答对于减少潜伏感染细胞的储库是至关重要的。该项目旨在将这些观察结果整合到概念上新颖的HIV- 1根除策略中,该策略基于帕比司他作为潜伏期逆转剂与聚乙二醇化IFNa-2a作为先天免疫激活剂相结合的治疗。我们假设,同时使用这两种药物导致先天免疫依赖性消除潜伏感染的细胞,其中病毒再活化是诱导。具体目标(SA)1将专注于进行一项试点临床试验,其中n=30名ART治疗的HIV-1患者将以2:1的比例随机分配至帕比司他和PEG-IFNa-2a治疗组,共4个1周周期,每个周期间隔3周观察期,或4个单独帕比司他治疗周期。在SA 2中,我们将研究联合治疗方案如何影响CD 4 T细胞相关的HIV-1 RNA、血浆RNA、HIV-1 DNA水平和携带有复制能力的HIV-1的细胞频率。SA 3旨在全面分析与病毒储库大小减少相关的免疫效应,使用新型高通量质谱法结合基因表达谱和功能测定。这项研究代表了在HIV-1病毒学、免疫学、药理学和临床患者护理方面具有互补专业知识的研究人员的跨学科合作,将为制定旨在根除HIV-1的临床策略提供大量信息。
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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Daniel R. Kuritzkes其他文献
Ultrasensitive and long-lasting bioluminescence immunoassay for point-of-care viral antigen detection
用于即时检验病毒抗原检测的超灵敏和持久的生物发光免疫测定法
- DOI:
10.1038/s41551-025-01405-9 - 发表时间:
2025-05-30 - 期刊:
- 影响因子:26.600
- 作者:
Sungwan Kim;Giwon Cho;Jaebaek Lee;Khushi Doshi;Supriya Gharpure;Jisan Kim;Juyong Gwak;Joseph M. Hardie;Manoj K. Kanakasabapathy;Hemanth Kandula;Prudhvi Thirumalaraju;Younseong Song;Hui Chen;Daniel R. Kuritzkes;Jonathan Z. Li;Athe M. Tsibris;Hadi Shafiee - 通讯作者:
Hadi Shafiee
Dominant CD4sup+/sup T cell receptors remain stable throughout antiretroviral therapy-mediated immune restoration in people with HIV
在接受抗逆转录病毒疗法介导的人类免疫缺陷病毒感染者免疫恢复期间,占优势的 CD4+T 细胞受体保持稳定。
- DOI:
10.1016/j.xcrm.2023.101268 - 发表时间:
2023-11-21 - 期刊:
- 影响因子:10.600
- 作者:
Alexis Sponaugle;Ann Marie K. Weideman;Jolene Ranek;Gatphan Atassi;JoAnn Kuruc;Adaora A. Adimora;Nancie M. Archin;Cynthia Gay;Daniel R. Kuritzkes;David M. Margolis;Benjamin G. Vincent;Natalie Stanley;Michael G. Hudgens;Joseph J. Eron;Nilu Goonetilleke - 通讯作者:
Nilu Goonetilleke
Willingness to trade-off years of life for an HIV cure – an experimental exploration of affective forecasting
- DOI:
10.1186/s12981-024-00640-5 - 发表时间:
2024-08-06 - 期刊:
- 影响因子:2.500
- 作者:
Ilona Fridman;Nir Eyal;Karen A. Scherr;Judith S. Currier;Kenneth A. Freedberg;Scott D. Halpern;Daniel R. Kuritzkes;Monica Magalhaes;Kathryn I. Pollak;Peter A. Ubel - 通讯作者:
Peter A. Ubel
Daniel R. Kuritzkes的其他文献
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{{ truncateString('Daniel R. Kuritzkes', 18)}}的其他基金
A Clinical Trial of Three Broadly Neutralizing Antibodies and Analytic Treatment Interruption in Early-Treated Children in Botswana
博茨瓦纳早期治疗儿童中三种广泛中和抗体和分析治疗中断的临床试验
- 批准号:
10764517 - 财政年份:2023
- 资助金额:
$ 190.85万 - 项目类别:
HIV-1 dynamics and evolution during trispecific broadly neutralizing antibody therapy
三特异性广泛中和抗体治疗期间的 HIV-1 动力学和进化
- 批准号:
10388267 - 财政年份:2021
- 资助金额:
$ 190.85万 - 项目类别:
HIV-1 dynamics and evolution during trispecific broadly neutralizing antibody therapy
三特异性广泛中和抗体治疗期间的 HIV-1 动力学和进化
- 批准号:
10599272 - 财政年份:2021
- 资助金额:
$ 190.85万 - 项目类别:
HIV-1 dynamics and evolution during trispecific broadly neutralizing antibody therapy
三特异性广泛中和抗体治疗期间的 HIV-1 动力学和进化
- 批准号:
10258850 - 财政年份:2021
- 资助金额:
$ 190.85万 - 项目类别:
A clinical trial to evaluate the impact of broadly neutralizing antibody VRC01 on HIV viral reservoir and maintenance of suppression in a cohort of early-treated children in Botswana
一项临床试验,旨在评估广泛中和抗体 VRC01 对博茨瓦纳早期治疗儿童队列中 HIV 病毒库的影响以及维持抑制
- 批准号:
10092914 - 财政年份:2018
- 资助金额:
$ 190.85万 - 项目类别:
A clinical trial to evaluate the impact of broadly neutralizing antibody VRC01 on HIV viral reservoir and maintenance of suppression in a cohort of early-treated children in Botswana
一项临床试验,旨在评估广泛中和抗体 VRC01 对博茨瓦纳早期治疗儿童队列中 HIV 病毒库的影响以及维持抑制
- 批准号:
10700262 - 财政年份:2018
- 资助金额:
$ 190.85万 - 项目类别:
A clinical trial to evaluate the impact of broadly neutralizing antibody VRC01 on HIV viral reservoir and maintenance of suppression in a cohort of early-treated children in Botswana
一项临床试验,旨在评估广泛中和抗体 VRC01 对博茨瓦纳早期治疗儿童队列中 HIV 病毒库的影响以及维持抑制
- 批准号:
10335240 - 财政年份:2018
- 资助金额:
$ 190.85万 - 项目类别:
A Pilot Clinical Trial for HIV-1 Eradication
根除 HIV-1 的试点临床试验
- 批准号:
9197496 - 财政年份:2015
- 资助金额:
$ 190.85万 - 项目类别:
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