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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：1 型人类免疫缺陷病毒 (HIV-1) 是一种感染免疫系统 CD4+ 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最终可能死亡。结果表明，联合抗逆转录病毒疗法在阻止感染个体中的 HIV-1 复制方面非常有效，尽管该疗法成功地将 HIV-1 复制抑制到临床无法检测到的水平。这是因为 HIV-1 在称为静息记忆 CD4+ T 细胞的 CD4+ T 细胞子集中持续处于沉默或潜伏状态，在这种潜伏状态下，这些受感染的细胞不会成为治疗的目标。抗逆转录病毒药物且无法被免疫系统消除，在 HIV-1 感染者中，潜伏感染的 CD4+ T 细胞的发现频率极低（每百万个静息记忆 CD4+ T 细胞中约有 1 个）。潜伏感染的细胞非常稳定，要求HIV-1感染者无限期地接受抗逆转录病毒治疗，因此，这一潜伏感染的CD4+群体。 T细胞是治愈HIV-1感染的主要障碍。制定消除潜伏感染细胞的策略是 NIH、NIAID 和 HIV-1 研究领域的一个主要重点，消除这些细胞的主要建议是“踢杀”方法，在这种方法中，潜伏感染的细胞被踢出。通过重新激活 HIV-1 产生的药物，这些细胞可以被免疫系统或病毒本身的细胞病变效应杀死。然而，最近的研究表明，这些药物单独使用时并不能显着逆转 HIV-1 感染者细胞中的潜伏期，我们的初步数据表明，这些潜伏期逆转药物的组合是有希望的。该提案旨在 (1) 优化潜伏期逆转药物的组合，(2) 确定这些组合的治疗是否会导致潜伏感染细胞的死亡，(3) 帮助解释。不和谐实验室模型系统的潜伏期和来自 HIV-1 感染者的真实潜伏感染细胞之间的差异。识别有效的潜伏期逆转药物的组合并了解这些组合是否会促进潜伏感染细胞的消除对于潜伏期研究和临床试验的未来规划非常重要，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潜伏感染细胞的理解。感染者体内 HIV-1 潜伏期的维持。