Probing mechanisms of reduced HIV reservoirs in an interferon-a clinical trial

干扰素临床试验中探索减少 HIV 储存的机制

• 批准号: 8603530
• 负责人: Una T O'Doherty
• 金额: $ 22.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603530
• 关键词: Address; Affect; Antigen Presentation; Automobile Driving; CD8B1 gene; Cells; Cessation of life; Chronic; Clinical Trials; Clinical Trials Design; Coculture Techniques; Cytotoxic T-Lymphocytes; DNA; Data; Epidemic; Frequencies; Future; Gagging; Genetic Transcription; HIV; HIV Antigens; Highly Active Antiretroviral Therapy; Histone Deacetylase Inhibitor; Immune; In Vitro; Interferons; Lead; Lymphocyte Function; Measures; Mediating; Modeling; Monitor; Patients; Phenotype; Positioning Attribute; Proteins; RNA; Relative (related person); Role; Sampling; Sampling Studies; Testing; Translations; Viral Load result; compare effectiveness; effective therapy; experience; immune clearance; in vitro Model; in vivo; insight; interest; interferon therapy; killings; perforin; protein expression; public health relevance; superinfection; trend

DESCRIPTION (provided by applicant): Interferon-?? (IFN-?) is known for its ability to restrict ongoing HIV replication, but with the advent of ART, interest in IFN-?'s activity against HIV waned. Exciting new data from a recent trial renews our interest as it suggests IFN-? may have activity against HIV reservoirs since integrated HIV DNA (but not total HIV DNA) was reduced in a subset of patients treated with IFN-? (pegylated interferon-?2A). This R21 proposal addresses a role for CTL as driving the decrease in HIV integration found with IFN-? therapy. Our rationale that IFN-? may enhance immune clearance is derived from the fact that HIV proteins can be expressed more efficiently from integrated HIV DNA than from unintegrated HIV DNA, which would lead to preferential clearance of integrated over unintegrated HIV DNA-the results found in vivo in the prior IFN-a trial. These findings led us to our overarching hypothesis: that IFN-? enhances immune clearance of the reservoir. We will use our latent model to further explore if IFN-? increases immune clearance by either making the reservoir more visible or by enhancing effector function. Our general approach is to purify CD4s and CD8s from ART infected patients and to treat these cells individually with IFN-? before coculture and then assess if reservoirs are reduced. We will compare these results to HDACi which are known to enhance HIV expression and are currently being tested for activity against HIV reservoirs in clinical trials. The effects of HDACi on antigen presentation and HIV specific CTL are unknown. We will dissect if the effects are on CD4s or CD8s and if HIV antigen expression, presentation or CTL function are enhanced by IFN-a. We will also compare and contrast IFN-? Responders and Nonresponders in the original trial to elucidate the essential steps to reservoir reduction. We are in a unique position to contribute to this question because of our expertise in measuring integrated HIV DNA and our ability to detect small changes in integration levels. We envision our study will lead to future better trial design and new insights that will be required for HIV eradication. Our specific aims are: Aim 1: Determine if IFN-? enhances clearance of latent cells in vitro and ex vivo by increasing HIV expression, antigen presentation, and/or CTL effectiveness and compare to the effects of HDACi to understand how IFN-? might reduce reservoirs. Aim 2: Examine if in vivo evidence in the prior IFN-a trial supports our model of CTL- mediated clearance.

性状（由申请人提供）：干扰素-？？(IFN-?)众所周知，它的能力，以限制正在进行的艾滋病毒复制，但随着ART的出现，在IFN-？的抗艾滋病毒活性减弱。 令人兴奋的新数据，从最近的试验更新我们的兴趣，因为它表明干扰素-？可能有活性对艾滋病毒水库，因为整合的艾滋病毒DNA（但不是总的艾滋病毒DNA）是减少在一个子集的患者治疗干扰素-？（聚乙二醇干扰素-？2A）。这个R21建议解决了CTL的作用，作为驱动与IFN-？疗法我们的理论是IFN-？可能增强免疫清除的原因是，整合的HIV DNA比未整合的HIV DNA更有效地表达HIV蛋白，这将导致整合的HIV DNA优先于未整合的HIV DNA被清除--这是之前IFN-a试验中体内发现的结果。这些发现使我们的首要假设：IFN-？增强储库的免疫清除。我们将使用我们的潜在模型，以进一步探讨，如果IFN-？通过使储库更明显或通过增强效应器功能来增加免疫清除。 我们的一般方法是纯化CD 4和CD 8从ART感染的患者，并单独治疗这些细胞与IFN-？然后进行共培养，然后评估储库是否减少。我们将这些结果与HDACi进行比较，HDACi已知可增强HIV表达，目前正在临床试验中测试其对HIV储库的活性。HDACi对抗原呈递和HIV特异性CTL的影响尚不清楚。 我们将分析IFN-α对CD 4或CD 8的影响，以及IFN-α是否增强了HIV抗原的表达、呈递或CTL功能。我们还将比较和对比IFN-？原始试验中的应答者和无应答者，以阐明减少储库的基本步骤。由于我们在测量整合的艾滋病毒DNA方面的专门知识以及我们检测整合水平的微小变化的能力，我们处于一个独特的地位，可以为这个问题做出贡献。我们设想我们的研究将导致未来更好的试验设计和新的见解，这将是根除艾滋病毒所必需的。我们的具体目标是：目标1：确定 IFN-？通过增加HIV表达、抗原呈递和/或CTL有效性增强体外和离体潜伏细胞的清除，并与HDACi的作用进行比较，以了解IFN-？可能会减少水库。 目的2：检查在先前的IFN-α试验中的体内证据是否支持我们的CTL介导的清除模型。