Targeting HIV persistence in CD4+ T memory stem cells

靶向 CD4 T 记忆干细胞中的 HIV 持久性

基本信息

批准号：
9321252
负责人：
Viviana A Simon
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-10 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321252
关键词：
AIDS/HIV problem Agreement Anti-Retroviral Agents Antiviral Agents Antiviral Therapy Architecture Biology CD4 Positive T Lymphocytes Cell Culture Techniques Cell Lineage Cells Characteristics Collaborations Cytometry DNA Data Disease Engineering Event Frequencies Generations Genetic Genetic Transcription Genome Genomics Goals HDAC1 gene HIV HIV Infections HIV Seropositivity Highly Active Antiretroviral Therapy Human IL2 gene Immune Immunologic Surveillance Infection Infection Control Integration Host Factors Interleukin-15 Intervention Knowledge Laboratories Life Maintenance Measures Memory Modeling Molecular Molecular Probes Nuclear Oligonucleotides Outcome Pathogenesis Pathway interactions Patients Persons Physiological Play Population Proliferating Property Proteins Proteome Proteomics Proviruses Reporter Research Reverse Transcription Role SIV Seeds Signal Transduction Source Stem cells T memory cell T-Lymphocyte Testing Therapeutic Time Viral Virus Virus Diseases base cytokine genetic makeup in vivo inhibitor/antagonist innovation memory CD4 T lymphocyte novel offspring programs public health relevance purge research study self-renewal stem volunteer

项目摘要

DESCRIPTION (provided by applicant): Eliminating HIV persistence is an obligated step to curing HIV/AIDS disease. Indeed, life-long highly active antiretroviral therapy is required since current antiviral drugs fail to eliminate the virus from HIV-infected patients. Despite intensive research there are no effective strategies to eliminate latent, transcriptionally silent HIV proviruses from HIV infected patients with well-controlled HIV infection. Emerging evidence suggest that CD4+ T memory stem cells (TSCM), the least differentiated of all CD4+ T cell memory populations, support HIV infection. There remains, however, a fundamental gap in our knowledge regarding the mechanisms and the extent of the impact of CD4+ T cells with stem like properties (TSMC) on establishment of HIV latency and persistence. Our preliminary data suggests that TSCM are fundamentally different from other CD4+ T memory cells. Since stem cells can renew and generate progeny cells for prolonged periods, we hypothesize that infected TSCM persist, maintain and seed CD4 T cells carrying latent proviruses. We will use mass-cytometry, 3D-FISH, proteomics and genomics to probe for the molecular mechanisms of latency establishment and maintenance specific for primary human CD4 T stem cells. We will define correlates of abortive, silent and productive infections in CD4+ TSCM, define the cellular programs specific for HIV persistence in CD4+ TSCM and probe for the CD4+ TSCM reservoir in HIV positive patients with spontaneous or HAART-assisted control of HIV infection. We will test to what extent a small number of integrations can seed the reservoir carrying the same latent provirus over multiple cell generations. Understanding the molecular mechanisms underlying latency establishment and maintenance in CD4+ TSCM is essential to develop targeted interventions aimed at shrinking and purging HIV persistence in CD4+ TSCM.

描述（由申请人提供）：消除艾滋病毒持续存在是治愈艾滋病毒/艾滋病疾病的必要步骤。事实上，尽管进行了大量研究，但目前的抗病毒药物仍无法消除艾滋病毒感染者体内的病毒，因此需要终身高效的抗逆转录病毒治疗。没有有效的策略来消除 HIV 感染得到良好控制的 HIV 感染患者体内潜伏的、转录沉默的 HIV 原病毒。新出现的证据表明，CD4+ T 记忆干细胞 (TSCM) 是分化程度最低的细胞。然而，关于具有干细胞样特性的 CD4+ T 细胞 (TSMC) 对 HIV 潜伏期和持久性的影响的机制和程度，我们的知识仍然存在根本性差距。我们的初步数据表明，TSCM 与其他 CD4+ T 记忆细胞有根本的不同，因为干细胞可以长时间更新和产生后代细胞，我们发现受感染的 TSCM 会持续存在、维持并接种携带潜伏原病毒的 CD4 T 细胞。质谱流式细胞仪、3D-FISH、蛋白质组学和基因组学，探索原代人 CD4 T 干细胞特异的潜伏期建立和维持的分子机制。我们将定义 CD4+ TSCM 中流产、沉默和生产性感染的相关性，定义细胞程序。特异性针对 CD4+ TSCM 中的 HIV 持续性，并探索自发或 HAART 辅助控制 HIV 感染的 HIV 阳性患者中的 CD4+ TSCM 储存库。我们将测试少量整合的程度。可以在多个细胞代中接种携带相同潜伏原病毒的储存库，了解 CD4+ TSCM 中潜伏期建立和维持的分子机制对于制定旨在减少和清除 CD4+ TSCM 中 HIV 持续存在的有针对性的干预措施至关重要。