Reactivation of latent HIV through TLR signaling

通过 TLR 信号重新激活潜伏的 HIV

基本信息

批准号：
8651886
负责人：
Alberto Bosque
金额：
$ 18.63万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-16 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651886
关键词：
Agonist Anti-Retroviral Agents Apoptosis Apoptotic Asthma Autoimmunity B-Lymphocytes BCL2 gene Bacterial Infections CD4 Positive T Lymphocytes Cell model Cells Cessation of life Clinical Trials Data Disease Elements Endothelial Cells Epithelial Cells Family Gene Expression Genetic Transcription Genus Mycobacterium Goals Gram-Negative Bacteria Gram-Positive Bacteria Growth Factor HIV HIV-1 Hypersensitivity Immune Immune system In Vitro Induction of Apoptosis Interleukin-2 Interleukin-7 Kinetics Knowledge Latent Virus Lead Length Life Ligands Lipoprotein (a)Lipoproteins Malignant Neoplasms Measures Mediating Mitogen-Activated Protein Kinases Natural Killer Cells Pathway interactions Peptides Pharmaceutical Preparations Play Predisposition Role Signal Pathway Signal Transduction Stimulus Study models T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Thinking Transcription Factor AP-1 Vaccine Adjuvant Viral Viral Genes Virus Virus Diseases acyl group analog design granulocyte in vitro Model inhibitor/antagonist latent infection macrophage mast cell memory CD4 T lymphocyte novel therapeutics public health relevance reactivation from latency receptor transcription factor

项目摘要

DESCRIPTION (provided by applicant): The existence of latent reservoirs of HIV-infected cells constitutes the major impediment towards viral eradication. HIV-1 latent reservoirs are small, but extremely long-lived. Latent infection is associated with undetectable levels of viral gene expression and appears to be non-cytopathic. However, upon reactivation, latent viruses enter an active mode of replication in which they are fully competent for spread and induction of disease. The current thinking in the field is that a combination of hypothetical drugs that will reactivate latent viruses (''anti-latency'' drugs), with present-day antiretroviral drugs, will be n effective approach toward viral eradication. Pam3C-SK4 is a synthetic triacylated lipopeptide analogue of naturally occurring lipoproteins in gram- negative bacteria, mycobacteria and some gram-positive bacteria; and it is used as a reference compound for TLR-2/1 activation. Using a previously described primary cell model for the study of HIV-1 latency, we have found that the triacylated lipopeptide Pam3C-SK4, but not other TLR agonists tested, is able to induce viral reactivation form latency in central memory CD4 T cells. Our main goal is to understand the signaling pathway activated by Pam3C-SK4 that leads to viral reactivation from latency in CD4 memory T cells. Furthermore, we will study whether Pam3C-SK4 increases the susceptibility to or accelerate the kinetics of apoptosis induction upon virus stimulation, as well as the ability to eliminate or reduce the latent reservoir in vitro. These studies will increase our knowledge on mechanisms of viral reactivation that can be applied to new therapeutic strategies toward HIV-1 eradication.

描述（由申请人提供）：HIV 感染细胞的潜在储存库的存在构成了根除病毒的主要障碍。 HIV-1 潜伏病毒库虽小，但寿命极长。潜伏感染与不可检测的病毒基因表达水平相关，并且似乎是非细胞病变的。然而，一旦重新激活，潜伏病毒就会进入活跃的复制模式，在这种模式下它们完全有能力传播和诱导疾病。该领域目前的想法是，将重新激活潜伏病毒的假设药物（“抗潜伏”药物）与现有的抗逆转录病毒药物相结合，将是根除病毒的有效方法。 Pam3C-SK4 是革兰氏阴性菌、分枝杆菌和一些革兰氏阳性菌中天然存在的脂蛋白的合成三酰化脂肽类似物；并用作 TLR-2/1 激活的参考化合物。使用先前描述的用于研究 HIV-1 潜伏期的原代细胞模型，我们发现三酰化脂肽 Pam3C-SK4（但不是其他测试的 TLR 激动剂）能够在中央记忆 CD4 T 细胞中诱导病毒从潜伏期重新激活。我们的主要目标是了解 Pam3C-SK4 激活的信号通路，该通路导致病毒从 CD4 记忆 T 细胞的潜伏期重新激活。此外，我们将研究 Pam3C-SK4 是否会增加对病毒刺激时细胞凋亡诱导的敏感性或加速其动力学，以及消除或减少体外潜伏储库。这些研究将增加我们对病毒再激活机制的了解，并将其应用于根除 HIV-1 的新治疗策略。