Towards Eradication: Reducing Proviral HIV DNA with Interferon-α Immunotherapy
走向根除:用干扰素-α 免疫疗法减少 HIV 病毒 DNA 前体
基本信息
- 批准号:8988529
- 负责人:
- 金额:$ 183.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-03 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnti-Retroviral AgentsBiological AssayBiopsyCD4 Positive T LymphocytesCD8B1 geneCellsChronicClinical TrialsControl GroupsDNAEffectivenessFc ReceptorFundingGene ExpressionGenesGoalsHIVHIV InfectionsHIV-1HumanImmuneImmunosuppressionImmunotherapyIndividualIntegration Host FactorsInterferon-alphaInterferonsInterruptionLaboratoriesLeadLengthLymphocyteMeasuresMediatingNatural Killer CellsPeripheral Blood Mononuclear CellPhenotypePhosphorylationPlasmaRNARandomized Clinical TrialsReportingResearchResidual stateT cell responseTestingTissuesViralViral reservoirViremiaVirus ReplicationWorkadaptive immunitybasecytotoxicitydigitalexperienceinnovationinsightmucosa-associated lymphoid tissueperipheral bloodpublic health relevancereconstitutionrectalresponse
项目摘要
DESCRIPTION (provided by applicant): Our long-term goal is to evaluate the effect of pegylated interferon (peg-IFN) α as an anti-HIV reservoir immunotherapy that could potentiate eradication strategies against HIV. The short-term goal of this proposal is to conduct a randomized clinical trial (RCT) to determine whether a 20-week treatment course with peg-IFN-α2b 1ug/kg/week, with or without a 4-week ART interruption, will reduce HIV-1 proviral DNA levels in circulating PBMC and gut mucosa-associated lymphoid tissue (MALT) in ART- treated long-term viral suppressed subjects with immune reconstitution. In our recently completed clinical trial (NCT00594880), we demonstrated that treatment with peg-IFN-α2a started on ART resulted in 12 week viral suppression during ART interruption (peg-IFN-α2a monotherapy) in 50% of the subjects, concurrently with activation of intrinsic anti-HIV genes, higher NK responses, and a significant reduction in integrated proviral HIV DNA (a measure of latent reservoir). In order to reproduce our findings, determine the requirement for viral reactivation to
trigger anti-HIV responses, and gather insights into mechanism of action, we propose to conduct a randomized clinical trial (RCT) to test our primary hypothesis that 20 weeks of treatment with peg-IFN-α2b (with or without HIV reactivation following ART interruption) will activate intrinsic and immune-mediated anti-HIV responses resulting in a reduction of integrated HIV DNA in chronically HIV-infected, immune-reconstituted individuals when compared to a control group of individuals undergoing comparable ART treatment in the absence of peg-IFN-α2b. We propose to test this hypothesis by addressing the following specific aims: Specific Aim 1: to assess the effectiveness of a 20-week course of peg-IFN-α2b to reduce measures of HIV reservoir by conducting an RCT to a) compare the change in integrated proviral HIV DNA/peripheral blood CD4+ T cell in ART suppressed subjects receiving peg-IFN-α2b treatment to an expected change of zero in the control group (primary endpoint); b) assess the requirement for viral replication (via short-term ART interruption) to activate immune mechanisms leading to the reduction of integrated HIV DNA; c) compare total and integrated HIV DNA levels in MALT-associated CD4+ T lymphocytes from rectal mucosal biopsies; d) compare levels of integrated DNA to other measures of viral reservoir (Q-VOA, ddPCR). Specific Aim 2: to characterize the anti-HIV intrinsic (host gene expression), innate and CD8 T-cell responses underlying changes in integrated HIV DNA following peg-IFN-α2b immunotherapy, as well as their correlation with secondary viral measures (ddPCR or Q-VOA).
描述(由申请人提供):我们的长期目标是评估聚乙二醇化干扰素(peg-IFN) α作为抗HIV库免疫疗法的效果,该疗法可以增强针对HIV的根除策略。该建议的短期目标是进行一项随机临床试验(RCT),以确定在ART治疗的长期病毒抑制的免疫重建患者中,每周一ug/kg的peg-IFN-α2b治疗20周,同时或不中断4周的ART治疗,是否会降低循环PBMC和肠道黏膜相关淋巴组织(MALT)中的HIV-1前病毒DNA水平。在我们最近完成的临床试验(NCT00594880)中,我们证明,在ART中断(peg-IFN-α2a单药治疗)期间,50%的受试者使用peg-IFN-α2a治疗导致12周的病毒抑制,同时激活内在抗HIV基因,提高NK反应,并显着降低整合前HIV DNA(一种潜在库的测量)。为了重现我们的发现,确定病毒再激活的需求
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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Luis J Montaner其他文献
Luis J Montaner的其他文献
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