Targeting the HIV-1 Reservoir in Myeloid Cells

靶向骨髓细胞中的 HIV-1 储存库

• 批准号: 10445309
• 负责人: JIN WANG
• 金额: $ 48.36万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-06 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445309
• 关键词: Apoptosis; Apoptotic; Autophagocytosis; Blood specimen; Brain; CD4 Positive T Lymphocytes; Cell Death; Cells; DNA; Data; Development; Ensure; HIV; HIV Infections; HIV-1; Human; Immune system; Immunologic Memory; In Vitro; Induction of Apoptosis; Infection; Inflammation; Inflammatory; Inflammatory Response; Lead; Memory; Microglia; Mus; Myelogenous; Myeloid Cells; Patients; Pharmaceutical Preparations; Regimen; Resistance; Safety; Specificity; T memory cell; T-Lymphocyte; Testing; Tissues; Viral; Virus; Work; base; chronic infection; cytokine; experimental study; humanized mouse; improved; in vivo; inhibition of autophagy; insight; lymphoid organ; macrophage; novel; preservation; reconstitution; success

ABSTRACT HIV is reverse-transcribed and integrated into the DNA of host cells, resulting in persistent infections that are difficult to clear. To date, there is no effective cure to clear the virus from HIV- infected patients. We have shown an approach to eradicate HIV infections by selective elimination of host cells harboring replication-competent HIV (SECH). The SECH treatment can clear HIV-1 in over 50% mice reconstituted with a human immune system, and in blood samples from HIV-1- infected patients. SECH can clear HIV-infection not only in CD4 T cells, but also in macrophages and microglia cells. Experiments are proposed to determine how to improve the efficacy and safety for SECH in clearing HIV-infection in the macrophage lineage: 1) To improve the efficacy and specificity in the killing of HIV-1-infected macrophages. We have found that increased viral reactivation leads to improved viral clearance in humanized mice. We will identify drugs that show greater potentials in virus reactivation that could lead to better HIV clearance. We will examine the inflammatory potentials for IDB and alternative LRAs in macrophages, and determine what inflammatory cytokines may need to be targeted; 2) To determine how to improve the efficacy and safety in the clearance of HIV reservoir in the macrophage lineage in lymphoid organs and in the brain of humanized mice. We will evaluate whether alternative agents can improve the clearance of HIV-1 in humanized mice in vivo. We will also determine whether optimum SECH regimens can induce limited and controllable inflammatory responses. Our proposed work will provide novel insights into how targeting apoptosis and autophagy regulates the clearance of HIV infection in the macrophage lineage. The studies will facilitate the development of SECH clear HIV-1 infection in lymphoid organs and in the brain to achieve complete eradication of HIV-1.

抽象的 HIV被逆转录并整合到宿主细胞的DNA中，导致持久性 难以清除的感染。迄今为止，还没有有效的治疗方法可以清除艾滋病病毒 感染的患者。我们已经展示了一种通过选择性消除来根除艾滋病毒感染的方法 携带有复制能力的 HIV (SICH) 的宿主细胞。 SECH治疗可以清除HIV-1 在超过 50% 的小鼠中重组了人类免疫系统，以及 HIV-1- 的血液样本中 感染的患者。 SECH 不仅可以清除 CD4 T 细胞中的 HIV 感染，还可以清除巨噬细胞中的 HIV 感染 和小胶质细胞。建议进行实验以确定如何提高功效和 SECH清除巨噬细胞系中HIV感染的安全性：1）提高疗效 以及杀死 HIV-1 感染的巨噬细胞的特异性。我们发现病毒增加 再激活可提高人源化小鼠的病毒清除率。我们将识别显示出的药物 病毒重新激活的潜力更大，可以更好地清除艾滋病毒。我们将检查 巨噬细胞中 IDB 和替代 LRA 的炎症潜力，并确定什么 可能需要针对炎症细胞因子； 2）确定如何提高功效 以及清除淋巴器官和巨噬细胞谱系中 HIV 储存库的安全性 在人源化小鼠的大脑中。我们将评估替代药物是否可以改善 人源化小鼠体内 HIV-1 的清除。我们还将确定是否最佳 SECH 治疗方案可以诱导有限且可控的炎症反应。我们提出的工作将 为靶向细胞凋亡和自噬如何调节 HIV 清除提供新见解 巨噬细胞谱系感染。这些研究将促进 SECH 的明确发展 HIV-1感染在淋巴器官和大脑中实现彻底根除HIV-1。