Targeting the HIV-1 Reservoir in Myeloid Cells

靶向骨髓细胞中的 HIV-1 储存库

• 批准号: 10326730
• 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/10326730
• 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反转录并整合到宿主细胞的DNA中，导致持续 难以清除的感染。迄今为止，还没有有效的治疗方法可以从HIV中清除病毒 感染的患者。我们已经通过选择性消除了一种消除HIV感染的方法 具有复制能力的HIV（SECH）的宿主细胞。 SECH治疗可以清除HIV-1 在超过50％的小鼠中，与人类免疫系统重组，在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，而且可以清除巨噬细胞中的HIV感染 和小胶质细胞。提出了实验来确定如何提高功效和 SECH在清除巨噬细胞谱系中的HIV感染方面的安全性：1）提高功效 和杀死HIV-1感染巨噬细胞的特异性。我们发现病毒增加 重新激活导致人性化小鼠的病毒清除率改善。我们将确定显示的药物 病毒重新激活的更大潜力可能导致更好的HIV清除。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 炎性细胞因子可能需要靶向； 2）确定如何提高功效 和在巨噬细胞器官中的巨噬细胞谱系中清除艾滋病毒储量的安全性和安全性 在人性化小鼠的大脑中。我们将评估替代代理是否可以改善 人体化小鼠在体内的清除。我们还将确定是否最佳SECH 方案可以诱导有限且可控的炎症反应。我们提出的工作将 提供有关靶向凋亡和自噬如何调节HIV清除hiv的新颖见解 巨噬细胞谱系中的感染。这些研究将促进SECH明确的发展 HIV-1感染淋巴器官和大脑中的感染，以完全消除HIV-1。