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.

概括目前有3,400万人在全球享有艾滋病毒的人，开发了一种诱导艾滋病毒功能的方式治愈是全球最佳健康优先事项。我们最近发现，1）广泛中和抗体能够为了有效地消除病毒储存库，以及2）IL-15超级飞行器ALT-803能够扭转病毒潜伏并激活体内天然杀伤细胞。因此，我们假设将alt-803与广泛的货车覆盖下的中和抗体可以清除潜在储层。调查这个有趣的想法 R21的特定目标1，我们将建立Alt-803在猕猴中重新激活潜在病毒的能力艾滋病毒模型。在特定目标2中，我们将确定ALT-803活化的NK细胞是否可以介导抗体 - 受依赖的细胞介导的感染细胞的细胞毒性。如果成功，我们将将Alt-803与广泛的在R33相中，在CARS覆盖下中和抗体。这些研究成功完成定义一种清除潜在储层的全新方法。