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Eradication of CNS HIV reservoirs through a first-in-class anti-tumor agent ONC201

通过一流的抗肿瘤药物 ONC201 根除 CNS HIV 储存库

基本信息

批准号：
10202458
负责人：
Yunlong Huang
金额：
$ 19.13万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202458
关键词：
AKT inhibition Advanced Malignant Neoplasm Aging Antiviral Agents Apoptosis Astrocytes Blood - brain barrier anatomy Brain CD34 gene Cell Culture System Cell Culture Techniques Cell Nucleus Cell Survival Cells Central Nervous System Infections Clinical Data Clinical Trials Control Groups Data Drug Kinetics Drug Targeting Encephalitis Family Future Gene Expression Glioma Goals Grant H3 K27M mutation HIV HIV-1 Hematologic Neoplasms Homeostasis Human Immune In Vitro Infection Laboratories Lymphoid Lymphoid Tissue MAPK3 gene Maintenance Mediating Microglia Modeling Modification Molecular Mus Neuraxis Neurons Normal Cell Oral Pathway interactions Pharmaceutical Preparations Phosphorylation Plasma Pre-Clinical Model Principal Component Analysis Publications Recurrence Regimen Research Safety Signal Transduction Site Solid Neoplasm T-Lymphocyte TNF gene TNF-related apoptosis-inducing ligand Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect Transgenic Mice Transgenic Model Transgenic Organisms United States National Institutes of Health Up-Regulation Viral Viral Load result Virus activating transcription factor antiretroviral therapy antitumor agent antitumor drug antitumor effect biological adaptation to stress cancer clinical trial cell type combat cytokine drug development drug discovery humanized mouse immunoregulation improved insight latent HIV reservoir macrophage memory CD4 T lymphocyte mouse model neoplastic cell nerve stem cell neuroAIDS novel pre-clinical therapy receptor single cell analysis single cell technology small molecule transcription factor tumor viral rebound

项目摘要

Project Summary/Abstract Despite combination antiretroviral therapy (ART), HIV-1 continues to form reservoirs in lymphoid, gut and central nervous system (CNS). The HIV-1 brain reservoir is a pool of long-lived cells, which include perivascular macrophages and microglia that can harbor replication-competent virus. Therapeutic interventions that can effectively eliminate HIV in these CNS cells are urgently needed. FOXO3a, a powerful transcription factor critical for aging and immune homeostasis, offers hope to eliminate HIV-1 reservoirs. Our previous publications have demonstrated that FOXO3a and cytokine TNF-related apoptosis-inducing ligand (TRAIL) target HIV-1-infected macrophages for apoptosis. Interestingly, there is an apparent lack of FOXO3a and TRAIL signaling in the CNS during HIV-1 invasion. The deficiency of FOXO3a signaling and TRAIL expression may inadvertently facilitate the forming of HIV-1 brain reservoirs. Therefore, FOXO3a may serve as a drug target to clear HIV-1-infected macrophage and microglia during HIV-1 infection of the CNS. Our long-term objective is to target FOXO3a/TRAIL pathway and make drug discoveries to improve treatment for people living with HIV-1. We will take advantage of a recent drug development that provided ONC201 as a potent and stable small molecule activator of FOXO3a/TRAIL pathway. ONC201 is orally active, has a wide safety margin, and can cross the blood-brain barrier with favorable pharmacokinetics. Moreover, ONC201 has shown efficacious antitumor effect in numerous solid tumors and hematological malignancies in preclinical models and in clinical trials. We have obtained ONC201 and shown for the first time that ONC201 has anti-viral effects in vitro and in a murine HIV-1 encephalitis model (Zhao et al, Antiviral Research, 2019). Furthermore, we have performed preliminary studies demonstrating that ONC201 potentiates the anti-viral effect of ART drug and delays viral rebound in vitro in macrophage cultures. We hypothesize that modulation of FOXO3a through the first-in-class anti-tumor drug ONC201 will induce TRAIL and facilitate ART leading to HIV-1 elimination in CNS reservoirs. In Aim 1, we will determine the utility of ART and ONC201 in HIV CNS eradication in the humanized CD34-engrafted IL-34-transgenic mice as a model for neuroHIV. In Aim 2, we will elucidate the pathways (mechanisms) responsible for ONC201-mediated viral clearance in macrophages, microglia, and T cells in relation to FOXO3a/TRAIL during ART. To achieve these aims, we will use a “state of the art” humanized mouse model and in vitro macrophage and T cell cultures and evaluate whether ONC201 and the standard ART can synergistically reduce the CNS viral load and delay viral rebound. The proposed studies will provide important proof-of-concept that endogenous FOXO3a could be harnessed by ONC201 to combat persistent and latent HIV-1 infection. Understanding the interactions between immune control of HIV-1 infection and ART will reveal new insights for the treatment of HIV-1 infection and its CNS complications.

项目总结/文摘