An IL-15 superagonist approach to clear the latent viral reservoir

IL-15 超级激动剂清除潜伏病毒库的方法

基本信息

批准号：
10065757
负责人：
Jonah B. Sacha
金额：
$ 48.57万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10065757
关键词：
Activated Natural Killer Cell Animal Model Animals Anti-Retroviral Agents Antiviral Agents B-Cell Lymphomas B-Lymphocytes Biological Assay Biological Response Modifiers CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Clinical Cytotoxic T-Lymphocytes Data Development Disease remission Goals HIV HIV Infections Health Priorities Helper-Inducer T-Lymphocyte Histone Deacetylase Inhibitor Homing Human Immunity Immunologic Deficiency Syndromes Immunologics In Vitro Interleukin-15 International AIDS Macaca Macaca mulatta Measures Mediating Memory Modality Modeling Monitor Natural Killer Cells Patients Peripheral Pharmaceutical Preparations Phase Phase I/II Clinical Trial Phase II Clinical Trials Publishing Recording of previous events Regulation Research SIV Safety Shock Societies Structure of germinal center of lymph node T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Viral Viral reservoir Virus Virus Latency Virus Replication antibody-dependent cell cytotoxicity antiretroviral therapy base cancer clinical trial efficacy testing global health humanized mouse immune clearance immune function in vivo latent HIV reservoir neutralizing antibody novel novel strategies pre-clinical purge rituximab small molecule working group

项目摘要

SUMMARY With 34 million people currently living with HIV worldwide, developing a modality to induce an HIV functional cure is a top global health priority. We have recently discovered that 1) broadly neutralizing antibodies are able to potently eliminate the viral reservoir, and 2) that an IL-15 superagonist, ALT-803, is able to both reverse viral latency and activate natural killer cells in vivo. Therefore, we hypothesize that combining ALT-803 with broadly neutralizing antibodies under cover of cART can clear the latent reservoir. To investigate this intriguing idea, in specific aim 1 of the R21, we will establish the ability of ALT-803 to reactivate latent virus in the macaque model of HIV. In specific aim 2, we will determine if ALT-803 activated NK cells can mediate antibody- dependent cell-mediated cytotoxicity on infected cells. If successful, we will combine ALT-803 with broadly neutralizing antibodies under cover of cART in the R33 phase. Successful completion of these studies could define an entirely new approach to clearing the latent reservoir.

概括目前全世界有 3400 万艾滋病毒感染者，开发一种诱导艾滋病毒功能的方法治愈是全球卫生的首要任务。我们最近发现 1) 广泛中和抗体能够有效消除病毒库，2) IL-15 超级激动剂 ALT-803 能够逆转病毒潜伏并激活体内自然杀伤细胞。因此，我们假设将 ALT-803 与广泛的 cART 覆盖下的中和抗体可以清除潜在的储库。为了研究这个有趣的想法， R21的具体目标1，我们将建立ALT-803重新激活猕猴体内潜伏病毒的能力艾滋病毒模型。在具体目标 2 中，我们将确定 ALT-803 激活的 NK 细胞是否可以介导抗体- 对受感染细胞的依赖性细胞介导的细胞毒性。如果成功，我们将把 ALT-803 与广泛的 R33 阶段 cART 覆盖下的中和抗体。成功完成这些研究可以定义一种全新的方法来清除潜在的储存库。