Regulation of Cell Death in HIV Reservoirs

HIV 储存库细胞死亡的调控

基本信息

批准号：
10674315
负责人：
JIN WANG
金额：
$ 60.92万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674315
关键词：
Aftercare Apoptosis Apoptotic Autophagocytosis BCL2 gene Biological Assay CASP3 gene Caspase Inhibitor Cell Death Cell Death Induction Cell Death Signaling Process Cell Survival Cells DNA Development Environment Epigenetic Process Family member Gene Expression Gene Expression Regulation Genes Genetic Transcription HIV HIV Infections HIV-1 IRF3 gene Immune Immune response Induction of Apoptosis Inflammasome Interruption Lymphoid Macrophage Measures Mediating Metabolic Pathway Molecular Myelogenous Myeloid Cells Pathway interactions Patients Persons RIPK1 gene RNA Regulation Reporting Resistance Resolution Role Sampling Shock Signal Transduction Stimulator of Interferon Genes T-Lymphocyte Techniques Testing Tissues Up-Regulation Vial device Viral Viral reservoir Virus antiretroviral therapy cellular targeting experimental study fitness humanized mouse improved in vivo latent HIV reservoir mouse model novel reactivation from latency response sensor single-cell RNA sequencing transcription factor transcriptome transcriptomics viral DNA viral RNA viral detection viral rebound

项目摘要

ABSTRACT: The combinational antiretroviral therapy is effective in suppressing HIV-1 replication. However, latent HIV reservoirs cannot be cleared by such antiretroviral therapy, as viral rebound develops rapidly after the treatment is interrupted in people living with HIV. The shock-and-kill approach to eliminate HIV-1 reservoirs is to induce viral reactivation using latency reversal agents and trigger cell death through virus-mediated cytopathic effects or immune-mediated clearance. However, shock-and-kill by latency reversal agents has not been shown to successfully reduce the viral reservoirs in HIV-1 patients. It has been reported that latency reversal agents can up-regulate pro-survival autophagy and anti-apoptotic molecules that counteract cell death signaling. Inhibition of these pro-survival mechanisms can promote the killing of HIV-1-infected cells, and facilitate the killing of HIV-1 reservoir cells during vial re-activation. Experiments are proposed to test hypothesis that cellular mechanisms that maintain the long-term persistence of HIV-1 reservoirs are important for protecting the reservoir cells against cell death, and targeting these cellular mechanisms can sensitize HIV-1 reservoirs to cell death during viral reactivation: 1) To determine the mechanisms for the specific induction of cell death in HIV-1 reservoirs in response to viral reactivation. The mechanisms for the induction of apoptosis and alternative cell death pathways in latent HIV-infected T cells by latency reversal agents will be tested; 2) To delineate the mechanisms that confer the resistance to cell death in HIV-1 reservoirs upon viral reactivation; and 3) To test whether targeting pro-survival mechanisms sensitizes HIV-1 reservoirs cells to cell death during viral re-activation. The studies will reveal novel molecular pathways that could be targeted to sensitize HIV-1 reservoirs to cell death, and facilitate the development of an effective approach to clear HIV-1 reservoirs.

抽象的：联合抗逆转录病毒疗法可有效抑制 HIV-1 复制。然而，随着病毒反弹的发展，这种抗逆转录病毒疗法无法清除潜伏的艾滋病毒储存库 HIV感染者的治疗中断后会迅速出现。震惊和杀戮的方法消除 HIV-1 储存库是使用潜伏逆转剂和触发器诱导病毒重新激活通过病毒介导的细胞病变效应或免疫介导的清除作用导致细胞死亡。然而，潜伏期逆转剂的休克和杀灭尚未被证明可以成功减少病毒 HIV-1 患者体内的储存库。据报道，潜伏期逆转剂可以上调促进生存的自噬和抵消细胞死亡信号传导的抗凋亡分子。抑制这些促生存机制可以促进杀死 HIV-1 感染的细胞，并且促进小瓶重新激活期间杀死 HIV-1 储存细胞。建议进行实验检验维持 HIV-1 长期存在的细胞机制的假设储存库对于保护储存库细胞免遭细胞死亡非常重要，并针对这些细胞细胞机制可以使 HIV-1 储存者在病毒重新激活期间对细胞死亡敏感：1) 确定 HIV-1 储存库中特异性诱导细胞死亡的机制到病毒重新激活。诱导细胞凋亡和替代性细胞死亡的机制将测试潜伏逆转剂在潜伏 HIV 感染 T 细胞中的通路； 2) 描绘在病毒重新激活时赋予 HIV-1 储存库细胞死亡抵抗力的机制； 3) 测试针对促生存机制是否会使 HIV-1 储存细胞对细胞敏感病毒重新激活期间死亡。这些研究将揭示新的分子途径旨在使 HIV-1 储存库对细胞死亡敏感，并促进有效的开发清除 HIV-1 病毒库的方法。