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

• 批准号: 8671884
• 负责人: Luis J Montaner
• 金额: $ 170.84万
• 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/8671884
• 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; Immune response; Immunosuppression; Immunotherapy; Individual; Integration Host Factors; 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 Markers; Viremia; Work; 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) ? 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-？50%的受试者接受了2a单药治疗），同时激活了固有的抗HIV基因、更高的NK反应以及整合的前病毒HIV DNA（潜在储存库的衡量标准）显着减少。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。