Ex vivo reversal of HIV-1 latency using PKC-agonist / HDAC inhibitor combinations

使用 PKC 激动剂/HDAC 抑制剂组合体外逆转 HIV-1 潜伏期

• 批准号: 8845663
• 负责人: Gregory Michael Laird
• 金额: $ 2.82万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2015-06-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845663
• 关键词: Acquired Immunodeficiency Syndrome; Agonist; Anti-Retroviral Agents; Bioinformatics; Biological Assay; Biological Models; CD4 Positive T Lymphocytes; Cell model; Cells; Cessation of life; Clinical Trials; Code; DNA; Data; Disulfiram; Drug Combinations; Evaluation; FDA approved; Frequencies; Future; Gene Expression; Genes; HIV-1; Histone Deacetylase Inhibitor; Immune; Immune system; In Vitro; Individual; Infection; Laboratories; Latent Virus; Left; Maintenance; Measures; Messenger RNA; National Institute of Allergy and Infectious Disease; Natural Immunity; Ontology; Pathway Analysis; Patients; Pharmaceutical Preparations; Play; Population; Production; Protein Kinase C; Proteins; RNA Splicing; Research; Resistance; Rest; Retroviridae; Role; Techniques; Transcript; United States National Institutes of Health; Untranslated RNA; Viral; Virus; Virus Activation; Work; aldehyde dehydrogenases; antiretroviral therapy; base; bryostatin; differential expression; digital; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; killings; memory CD4 T lymphocyte; public health relevance; research study; response; small molecule; success; theories; transcriptome sequencing

 DESCRIPTION (provided by applicant): Human immunodeficiency virus type-1 (HIV-1) is a retrovirus that infects CD4+ T cells of the immune system. If left untreated, HIV-1 infected individuals will progress to AIDS and may ultimately die as a result. Combination antiretroviral therapy is extremely effective at stopping the replication of HIV-1 in infected individuals. Despit the success of this therapy at suppressing HIV-1 replication to clinically undetectable levels, antiretroviral therapy is not curative. This is due to the persistence of HIV-1 in a silent, or latnt, state within a subset of CD4+ T cells known as resting memory CD4+ T cells. In this latent state, these infected cells are not targeted by antiretroviral drugs and cannot be eliminated by the immune system. In HIV-1 infected individuals, latently infected CD4+ T cells are found at extremely low frequencies (~1 per million resting memory CD4+ T cells). However, this population of latently infected cells is very stable, demanding that HIV-1 infected individuals remain on antiretroviral therapy indefinitely. Therefore, this population of latently infected CD4+ T cells is the main barrier to curing HIV-1 infection. Developing strategies to eliminate latently infected cells is a major focus of the NIH, NIAID, and the HIV-1 research field. A leading proposal to eliminate these cells is the "kick and kill" approach. In this approach, latently infected cells are kicked out of their latent state by a drug that reactivates HIV-1 production. After these cells are reactivated, they can be killed by the immune system or by the cytopathic effects of the virus itself. Using in vitro models of HIV-1 latency, a number of candidate latency-reversing drugs have been identified. However, recent studies indicate that these agents do not substantially reverse latency in cells from HIV-1 infected individuals when used individually. Promisingly, our preliminary data indicate that combinations of these latency-reversing drugs are very effective on cells from HIV-1 infected individuals. This proposal aims to (1) optimize combinations of latency-reversing drugs, (2) determine whether treatment with these combinations leads to the death of latently infected cells, (3) help explain the discordance between laboratory model systems of latency and bona fide latently infected cells from HIV-1 infected individuals. Identifying combinations of effective latency-reversing drugs and understanding whether these combinations drive the elimination of latently infected cells is important to latency research and the future planning of clinical trials. Understanding the differences between model cells and bona fide latently infected cells will deepen our understanding of the maintenance of HIV-1 latency in infected individuals.

 描述（由申请方提供）：人类免疫缺陷病毒1型（HIV-1）是一种感染免疫系统CD 4 + T细胞的逆转录病毒。如果不及时治疗，HIV-1感染者将发展为艾滋病，并可能最终死亡。联合抗逆转录病毒疗法在阻止感染者体内HIV-1复制方面非常有效。尽管这种疗法成功地将HIV-1复制抑制到临床检测不到的水平，但抗逆转录病毒疗法并不能治愈。这是由于HIV-1在称为静息记忆CD 4 + T细胞的CD 4 + T细胞亚群中持续处于沉默或latnt状态。在这种潜伏状态下，这些受感染的细胞不会被抗逆转录病毒药物靶向，也不能被免疫系统清除。在HIV-1感染的个体中，潜伏感染的CD 4 + T细胞的频率极低（每百万个静息记忆CD 4 + T细胞中约1个）。然而，这种潜伏感染的细胞群体非常稳定，要求HIV-1感染者无限期地接受抗逆转录病毒治疗。因此，这群潜伏感染的CD 4 + T细胞是治疗HIV-1感染的主要屏障。 制定消除潜伏感染细胞的策略是NIH，NIAID和HIV-1研究领域的主要焦点。消除这些细胞的一个主要建议是“踢和杀”的方法。在这种方法中，潜伏感染的细胞被重新激活HIV-1生产的药物踢出潜伏状态。在这些细胞被重新激活后，它们可以被免疫系统或病毒本身的细胞病变效应杀死。使用HIV-1潜伏期的体外模型，已经鉴定了许多候选的潜伏期逆转药物。然而，最近的研究表明，当单独使用时，这些药物不会显著逆转HIV-1感染个体细胞中的潜伏期。 令人鼓舞的是，我们的初步数据表明，这些潜伏期逆转药物的组合对HIV-1感染者的细胞非常有效。该提案旨在（1）优化逆转潜伏期药物的组合，（2）确定这些组合的治疗是否导致潜伏感染细胞的死亡，（3）帮助解释潜伏期的实验室模型系统与来自HIV-1感染个体的真正潜伏感染细胞之间的不一致性。 确定有效的潜伏逆转药物的组合，并了解这些组合是否驱动潜伏感染细胞的消除，对于潜伏期研究和未来的临床试验规划非常重要。了解模型细胞和真正的潜伏感染细胞之间的差异将加深我们对感染个体中HIV-1潜伏期维持的理解。