Towards Eradication: Reducing Proviral HIV DNA with Interferon-a Immunotherapy

描述(申请人提供)：我们的长期目标是评估聚乙二醇化干扰素(peg-干扰素)的效果？作为一种抗艾滋病毒的蓄水池，可以加强根除艾滋病毒的战略。这项建议的短期目标是进行一项随机临床试验(RCT)，以确定在接受ART治疗的长期病毒抑制免疫重建患者中，在接受或不接受ART干预的情况下，20周的疗程是否会降低循环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，我们证明了在ART中断期间(PEG-干扰素-2a单独治疗)，开始接受抗逆转录病毒治疗的患者中，有50%的受试者在12周内受到病毒抑制，同时固有的抗HIV基因被激活，更高的NK应答，以及整合前病毒DNA(潜伏期的衡量标准)显著减少。为了重现我们的发现，确定病毒重新激活的要求 为了触发抗HIV反应，并收集对作用机制的见解，我们提议进行一项随机临床试验(RCT)来检验我们的主要假设，即20周的PEG-IFN-？2B治疗(在ART中断后有或没有HIV重新激活)将激活固有的和免疫介导的抗HIV反应，导致慢性HIV感染、免疫重建的个体中整合的HIV DNA减少，与在没有PEG-IFN-？2B的情况下接受类似ART治疗的对照组相比。我们建议通过解决以下特定目标来验证这一假说：具体目标1：通过进行随机对照试验，评估为期20周的peg-干扰素-2b疗程以减少HIV储备量的有效性；a)比较接受peg-干扰素-2b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(主要终点)的预期零变化；b)评估病毒复制的需求(通过短期ART阻断)以激活导致整合HIV DNA减少的免疫机制；C)比较直肠粘膜活检组织中与MALT相关的CD4+T淋巴细胞中HIV DNA的总水平和整合水平；d)将整合DNA水平与其他衡量病毒库的指标(Q-VOA、ddPCR)进行比较。具体目的2：研究在聚乙二醇化干扰素-2B免疫治疗后，整合的HIV DNA的变化所引起的抗HIV固有(宿主基因表达)、先天和CD8 T细胞应答的特征，以及它们与二次病毒措施(ddPCR或Q-VOA)的相关性。

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).