Towards Eradication: Reducing Proviral HIV DNA with Interferon-a Immunotherapy
走向根除:用干扰素-a 免疫疗法减少 HIV 病毒 DNA 前体
基本信息
- 批准号:8671884
- 负责人:
- 金额:$ 170.84万
- 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-1HumanImmuneImmune responseImmunosuppressionImmunotherapyIndividualIntegration Host FactorsInterferonsInterruptionLaboratoriesLeadLengthLymphocyteMeasuresMediatingNatural Killer CellsPeripheral Blood Mononuclear CellPhenotypePhosphorylationPlasmaRNARandomized Clinical TrialsReportingResearchResidual stateT cell responseTestingTissuesViralViral MarkersViremiaWorkbasecytotoxicitydigitalexperienceinnovationinsightmucosa-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) ? 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-?2b 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-?2a started on ART resulted in 12 week viral suppression during ART interruption (peg-IFN-?2a 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-?2b (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-?2b. 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-?2b 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-?2b 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-?2b 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干扰素(PEG-IFN)的效果?作为一种抗艾滋病病毒水库免疫疗法,可以加强对艾滋病病毒的根除战略。本建议的短期目标是进行随机临床试验(RCT),以确定是否与聚乙二醇干扰素-?2b 1ug/kg/周,有或没有4周ART中断,将降低ART治疗的长期病毒抑制受试者中循环PBMC和肠道粘膜相关淋巴组织(MALT)中的HIV-1前病毒DNA水平,伴有免疫重建。在我们最近完成的临床试验(NCT 00594880),我们证明了治疗聚乙二醇干扰素-?2a开始抗逆转录病毒治疗导致12周的病毒抑制在抗逆转录病毒治疗中断(聚乙二醇干扰素-?2a单药治疗),同时激活了内在的抗HIV基因,NK应答更高,整合的前病毒HIV DNA(潜伏库的一种衡量标准)显著减少。为了重现我们的发现,确定病毒再激活的要求,
触发抗艾滋病毒反应,并收集到的行动机制的见解,我们建议进行随机临床试验(RCT),以检验我们的主要假设,20周的治疗与聚乙二醇干扰素-?2b(有或没有艾滋病毒再激活后,ART中断)将激活内在的和免疫介导的抗艾滋病毒反应,导致减少整合的艾滋病毒DNA在慢性艾滋病毒感染,免疫重建的个人相比,对照组的个人进行可比的ART治疗的情况下,聚乙二醇干扰素-?2b.我们建议通过解决以下具体目标来检验这一假设:具体目标1:评估20周的聚乙二醇干扰素-?2b通过进行随机对照试验减少HIV储库的测量,a)比较接受聚乙二醇-IFN-?2b治疗至对照组预期变化为零(主要终点); B)评估病毒复制的要求c)比较来自直肠粘膜活检的MALT相关的CD 4 + T淋巴细胞中的总HIV DNA水平和整合的HIV DNA水平; d)将整合的DNA水平与病毒储库的其他测量(Q-VOA,ddPCR)进行比较。具体目标二:表征抗HIV内在(宿主基因表达),先天性和CD 8 T细胞反应的变化,在整合的HIV DNA聚乙二醇干扰素-?2b免疫疗法,以及它们与二级病毒措施(ddPCR或Q-VOA)的相关性。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Luis J Montaner其他文献
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