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。进行一项随机临床试验（RCT），以确定聚乙二醇干扰素α2b 1ug/kg/周的 20 周治疗疗程，无论有或没有 4 周 ART 中断，是否会减少在 ART 长期病毒抑制且免疫重建的受试者中，循环 PBMC 和肠粘膜相关淋巴组织 (MALT) 中的 HIV-1 前病毒 DNA 水平在我们最近完成的临床试验 (NCT00594880) 中，我们证明了聚乙二醇干扰素治疗。 -α2a 开始 ART 导致 50% 的受试者在 ART 中断（peg-IFN-α2a 单药治疗）期间出现 12 周的病毒抑制，同时激活内在抗 HIV 基因、更高的 NK 反应以及整合的前病毒 HIV DNA（潜伏病毒库的衡量标准）显着减少。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，并深入了解作用机制，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、免疫重建个体中的整合 HIV DNA 减少，与在缺乏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：通过开展随机对照试验来评估 20 周的 peg-IFN-α2b 疗程对减少 HIV 储存的有效性。 a) 将接受 peg-IFN-α2b 治疗的 ART 抑制受试者中整合的前病毒 HIV DNA/外周血 CD4+ T 细胞的变化与对照组中预期的零变化进行比较（主要终点）；评估病毒复制的需要（通过短期 ART 中断）以激活导致整合 HIV DNA 减少的免疫机制； c) 比较直肠粘膜活检中 MALT 相关 CD4+ T 淋巴细胞的总 HIV DNA 水平和整合 HIV DNA 水平；将整合 DNA 水平与其他病毒库指标（Q-VOA、ddPCR）进行比较。 具体目标 2：表征整合 HIV DNA 变化背后的抗 HIV 内在（宿主基因表达）、先天和 CD8 T 细胞反应。 peg-IFN-α2b 免疫治疗后的情况，以及它们与二级病毒检测（ddPCR 或 Q-VOA）的相关性。