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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.

总结目前全世界有3400万人感染艾滋病毒，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地消除病毒储库，和2）IL-15超激动剂ALT-803能够逆转病毒储库，潜伏和激活体内自然杀伤细胞。因此，我们假设ALT-803与广泛的 cART覆盖下的中和抗体可以清除潜在的水库。为了研究这个有趣的想法，在 R21的特定目的1，我们将确定ALT-803在猕猴中重新激活潜伏病毒的能力艾滋病模型。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-NK细胞。依赖于细胞介导的对感染细胞的细胞毒性。如果成功，我们将联合收割机ALT-803与广泛的在R33阶段，在cART的掩护下中和抗体。成功完成这些研究可以定义了一种全新的方法来清除潜在的水库。