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

• 批准号: 8988529
• 负责人: Luis J Montaner
• 金额: $ 183.73万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8988529
• 关键词: Address; Anti-Retroviral Agents; Biological Assay; Biopsy; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chronic; Clinical Trials; Control Groups; DNA; Effectiveness; Fc Receptor; Funding; Gene Expression; Genes; Goals; HIV; HIV Infections; HIV-1; Human; Immune; Immunosuppression; Immunotherapy; Individual; Integration Host Factors; Interferon-alpha; Interferons; Interruption; Laboratories; Lead; Length; Lymphocyte; Measures; Mediating; Natural Killer Cells; Peripheral Blood Mononuclear Cell; Phenotype; Phosphorylation; Plasma; RNA; Randomized Clinical Trials; Reporting; Research; Residual state; T cell response; Testing; Tissues; Viral; Viral reservoir; Viremia; Virus Replication; Work; adaptive immunity; base; cytotoxicity; digital; experience; innovation; insight; mucosa-associated lymphoid tissue; peripheral blood; public health relevance; reconstitution; rectal; response

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 储库免疫疗法的效果，该疗法可以增强针对 HIV 的根除策略。该提案的短期目标是进行一项随机临床试验（RCT），以确定在有或没有4周ART中断的情况下，使用peg-IFN-α2b 1ug/kg/周的20周治疗过程是否会降低经过ART治疗的长期病毒抑制的免疫受试者中循环PBMC和肠粘膜相关淋巴组织（MALT）中的HIV-1前病毒DNA水平。 重构。在我们最近完成的临床试验 (NCT00594880) 中，我们证明，在 ART 开始使用 peg-IFN-α2a 治疗时，50% 的受试者在 ART 中断期间（peg-IFN-α2a 单药治疗）实现了 12 周的病毒抑制，同时激活了内在抗 HIV 基因、提高了 NK 反应，并显着减少了整合的前病毒 HIV DNA（潜伏期病毒 DNA 的测量）。 水库）。为了重现我们的发现，确定病毒重新激活的要求 触发抗 HIV 反应，并收集对作用机制的见解，我们建议进行一项随机临床试验 (RCT) 来检验我们的主要假设，即使用 peg-IFN-α2b 治疗 20 周（ART 中断后有或没有 HIV 再激活）将激活内在的和免疫介导的抗 HIV 反应，导致慢性 HIV 感染者中整合的 HIV DNA 减少， 与在没有 peg-IFN-α2b 的情况下接受类似 ART 治疗的对照组个体进行比较。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 peg-IFN-α2b 疗程对减少 HIV 储存量的有效性，方法是进行随机对照试验：a) 将接受 peg-IFN-α2b 治疗的 ART 抑制受试者中综合前病毒 HIV DNA/外周血 CD4+ T 细胞的变化与对照组中预期变化为零的变化进行比较 （主要终点）； b) 评估病毒复制的需要（通过短期 ART 中断）以激活免疫机制，从而减少整合的 HIV DNA； c) 比较直肠粘膜活检中 MALT 相关 CD4+ T 淋巴细胞的总 HIV DNA 水平和综合 HIV DNA 水平； d) 将整合 DNA 的水平与病毒库的其他测量值（Q-VOA、ddPCR）进行比较。具体目标 2：表征抗 HIV 内在（宿主基因表达）、先天和 CD8 T 细胞反应，这些反应是 peg-IFN-α2b 免疫治疗后整合 HIV DNA 变化的基础，以及它们与二级病毒测量（ddPCR 或 Q-VOA）的相关性。