An Ex Vivo Model of HIV-1 Latency and Reactivation using Primary Memory Cells

使用原代记忆细胞的 HIV-1 潜伏期和再激活的离体模型

• 批准号: 8019124
• 负责人: VICENTE PLANELLES
• 金额: $ 37.08万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019124
• 关键词: Agonist; Antigens; Area; Biological Process; Biology; CD4 Positive T Lymphocytes; Cells; Effector Cell; Elements; Event; Experimental Models; Future; Gene Expression; Genes; Goals; HIV; HIV-1; Human; Individual; Infection; Inflammation; Inflammatory; Knowledge; Latent Virus; Life; Memory; Modeling; Molecular; Physiological; Process; Proviruses; Regulation; Relative (related person); Signal Pathway; Signal Transduction; Stimulus; Study models; System; T memory cell; T-Lymphocyte Subsets; Trans-Activators; Vesicular stomatitis Indiana virus; Viral; Viral Genes; Virus; Virus Latency; cell type; cytokine; in vivo; latent infection; novel; permissiveness; public health relevance; reactivation from latency; transcription factor; translational study; Agonist; Antigens; Area; Biological Process; Biology; CD4 Positive T Lymphocytes; Cells; Effector Cell; Elements; Event; Experimental Models; Future; Gene Expression; Genes; Goals; HIV; HIV-1; Human; Individual; Infection; Inflammation; Inflammatory; Knowledge; Latent Virus; Life; Memory; Modeling; Molecular; Physiological; Process; Proviruses; Regulation; Relative (related person); Signal Pathway; Signal Transduction; Stimulus; Study models; System; T memory cell; T-Lymphocyte Subsets; Trans-Activators; Vesicular stomatitis Indiana virus; Viral; Viral Genes; Virus; Virus Latency; cell type; cytokine; in vivo; latent infection; novel; permissiveness; public health relevance; reactivation from latency; transcription factor; translational study

DESCRIPTION (provided by applicant): The proposed studies use a novel experimental model of viral latency and reactivation that utilizes primary memory cells as targets. Using this system, we plan to understand in detail the mechanisms that HIV-1 uses to establish latency in vivo, as well as the physiological signals that trigger viral reactivation. Knowledge from these areas will be applicable in future translational studies that will seek compounds mimicking or antagonizing the relevant signaling pathways, with the ultimate goal of destroying the latent reservoir. PUBLIC HEALTH RELEVANCE: HIV-1 in infected individuals establishes a relatively small, but long-lived reservoir of latently infected cells. Latent infection is associated with low or no viral gene expression and, accordingly, appears to be non-cytopathic. Latent viruses can undergo reactivation, giving rise to new productive infections that carry full pathogenic potential. The cell type that harbors this long-lived, latent viral reservoir is thought to consist of quiescent memory T cells. We present a novel ex-vivo model for the study HIV latency as well as its reactivation. This model faithfully recapitulates salient features of the in vivo latent reservoir. For example, latent proviruses in this system are devoid of any detectable gene expression, yet, they are perfectly competent for gene expression when reactivated by a number of external stimuli. This model uses primary, human CD4+ lymphocytes and viral integration is polyclonal. This powerful, yet straighforward experimental system will allow us to (i) assess the relative permissivenes of various CD4+ T cell subsets to harbor latent proviruses; (ii) explore signaling pathways that may preclude the establishment of latent infections and/or induce reactivation of latent proviruses; and (iii) explore the use of select agonists and antagonists of the relevant signaling pathways to experimentally manipulate latency and reactivation. Ultimately, HIV-1 eradication will require a profound understanding of the biological processes that control entry and exit from latency.

描述（由申请人提供）：拟议的研究使用了一种新型的病毒潜伏期和重新激活的实验模型，该模型利用主要的记忆细胞作为目标。使用该系统，我们计划详细了解HIV-1在体内建立潜伏期的机制，以及触发病毒重新激活的生理信号。这些领域的知识将适用于将来的翻译研究，该研究将寻求模仿或对抗相关信号通路的化合物，并最终目的是破坏潜在的储层。 公共卫生相关性：受感染者的HIV-1建立了一个相对较小但长期寿命的潜在感染细胞的储层。潜在感染与低病毒基因表达相关，因此似乎是非胞质的。潜在病毒会经历重新激活，从而引起新的生产感染，这些感染具有全部致病潜力。持有这种长期寿命的潜在病毒储层的细胞类型被认为由静止的记忆T细胞组成。我们提出了一种新型的用于研究HIV潜伏期及其重新激活的前体内模型。该模型忠实地概括了体内潜在储层的显着特征。例如，该系统中的潜在病毒没有任何可检测的基因表达，但是，当许多外部刺激重新激活时，它们具有基因表达的能力。该模型使用主要的人CD4+淋巴细胞，病毒整合是多克隆的。这个功能强大但直截了当的实验系统将使我们能够（i）评估各种CD4+ T细胞亚群的相对允许剂，以避开潜在的预科病毒； （ii）探索可能排除潜在感染和/或引起潜在病毒重新激活的信号通路； （iii）探索相关信号通路的精选激动剂和拮抗剂的使用，以实验操纵潜伏期和重新激活。 最终，消除HIV-1将需要对控制进入和退出潜伏期的生物学过程有深刻的了解。