The contribution of Tcell tolerance to latent HIV infection

T细胞耐受性对HIV潜伏感染的贡献

基本信息

批准号：
8597410
负责人：
Joseph K Wong
金额：
--
依托单位：
VETERANS AFFAIRS MED CTR SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-10-01 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8597410
关键词：
Address Aftercare Antiviral Agents Attenuated Biological Assay Blood Blood Circulation CD4 Positive T Lymphocytes Cardiovascular Diseases Cardiovascular system Cell Count Cell model Cells Cessation of life Characteristics Chronic Clinical Coculture Techniques Complex CpG Islands Cytotoxic T-Lymphocyte-Associated Protein 4 DNA DNA Markers Data Development Disease Drug usage Environment Epigenetic Process Evolution Exhibits Failure Foundations Frequencies Funding Future Gene Expression Genes Gut associated lymphoid tissue HIV HIV Infections HIV therapy HIV-1 Health Hepatic Highly Active Antiretroviral Therapy IL2 gene Immune response In Vitro Individual Institution Intervention Kidney Kidney Diseases Knowledge Lead Life Light Link Liver diseases Location Malignant Neoplasms Measures Methylation Modeling Modification Molecular Molecular Target Molecular Weight Myocardial Infarction Nature Pathologic Patients Pattern Peripheral Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phenotype Ploidies RNA RNA Splicing Recurrent disease Relative (related person)Reporting Repression Research Residual state Rest Shelter facility Signal Transduction Sorting - Cell Movement Stimulus Stroke T cell anergy T memory cell T-Cell Activation T-Lymphocyte Testing Time Veterans Viral Viral Genes Viral Load result Viremia Virus Virus Latency Work anergy antiretroviral therapy attenuation base design exhaust exhaustion immune activation in vivo latent infection memory CD4 T lymphocyte novel peripheral blood population based programs promoter purge receptor research study restoration viral DNA

项目摘要

DESCRIPTION (provided by applicant): HIV-1 persists in patients despite years of suppressive treatment with antiretroviral therapy (ART) and results in disease relapse when treatment is interrupted. One major barrier to treatment eradication is a reservoir of latently infected CD4+ T-cells. Whether these latently infected cells give rise to low-level ongoing replication or episodically activate and produce virus is controversial but this viral persistence likely contributes to ongoing immuno-pathologic effects that include incomplete T-cell restoration and the global immune activation that are implicated in HIV associated cardiovascular, renal and hepatic disease even among those on highly active antiretroviral therapy (HAART). It has also been recently recognized that despite expressing some markers of T-cell activation, T-cells from HIV infected patients also exhibit markers of T-cell exhaustion or tolerance that may underlie the insufficiency of the immune response against HIV-1. Our work from the previous funding cycle suggests that the latent viral reservoir may be heterogeneous in composition in vivo and the molecular mechanisms underlying viral latency are likely complex. We find that both T-cells in the gut and those in the blood exhibit very low HIV expression levels despite high levels of T-cell activation. One unifying mechanism for the attenuated expression of HIV could be the T-cell exhaustion that appears to accompany HIV infection. Our preliminary data suggest that, paradoxically, after successful viral suppression on ART, the proportion of cells expressing CTLA-4, a marker of T-cell anergy, increases. In the current proposal we will investigate evolution of the cellular reservoir of virus from patients initiating therapy during chronic HIV infection by examining individual CD4 populations based on presence or absence of markers of activation and anergy. We will test the novel hypothesis that tolerance acquired as a byproduct of chronic HIV infection, attenuates viral expression and gives rise to the paradoxical retention of large numbers of cells with latent HIV infection during suppressive therapy. We will determine whether epigenetic modification of the HIV LTR coincides with epigenetic modification of promoters of genes associated with T-cell activation. Finally, we will examine the effects of agents designed to reactivate HIV from latency or that reverse T-cell anergy on virus expression from T-cells obtained from patients on suppressive therapy in order to form the foundation for future interventions to purge the latent reservoir.

描述（由申请人提供）：尽管经过多年的抗逆转录病毒治疗 (ART) 抑制治疗，HIV-1 仍然在患者体内持续存在，并且当治疗中断时会导致疾病复发。根除治疗的一个主要障碍是潜伏感染的 CD4+ T 细胞库。这些潜伏感染的细胞是否引起低水平的持续复制或偶尔激活并产生病毒尚有争议，但这种病毒的持续存在可能会导致持续的免疫病理效应，包括与 HIV 相关的 T 细胞恢复不完整和整体免疫激活相关的心血管、肾脏和肝脏疾病，甚至在那些接受高效抗逆转录病毒治疗 (HAART) 的患者中也是如此。最近还认识到，尽管表达一些 T 细胞激活标记，HIV 感染患者的 T 细胞也表现出 T 细胞耗竭或耐受标记，这可能是针对 HIV-1 的免疫反应不足的原因。我们在上一个资助周期的工作表明，体内潜伏病毒库的成分可能是异质的，并且病毒潜伏期的分子机制可能很复杂。我们发现，尽管 T 细胞激活水平很高，但肠道和血液中的 T 细胞都表现出非常低的 HIV 表达水平。 HIV 表达减弱的一种统一机制可能是伴随 HIV 感染而来的 T 细胞耗竭。我们的初步数据表明，矛盾的是，在成功抑制 ART 病毒后，表达 CTLA-4（T 细胞无反应性标志物）的细胞比例却增加了。在当前的提案中，我们将根据激活和无反应标记物的存在或不存在来检查个体 CD4 群体，从而研究慢性 HIV 感染期间开始治疗的患者的病毒细胞库的演变。我们将检验新的假设，即作为慢性 HIV 感染的副产品而获得的耐受性，会减弱病毒表达，并导致在抑制治疗期间大量潜伏 HIV 感染的细胞滞留。我们将确定 HIV LTR 的表观遗传修饰是否与 T 细胞激活相关基因启动子的表观遗传修饰一致。最后，我们将研究旨在重新激活潜伏期 HIV 或逆转 T 细胞对从接受抑制治疗的患者获得的 T 细胞的病毒表达无反应性的药物的效果，以便为未来清除潜伏病毒库的干预措施奠定基础。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exogenous and endogenous hyaluronic acid reduces HIV infection of CD4(+) T cells.

DOI：
10.1038/icb.2014.50
发表时间：
2014-10
期刊：
IMMUNOLOGY AND CELL BIOLOGY
影响因子：
4
作者：
Li, Peilin;Fujimoto, Katsuya;Bourguingnon, Lilly;Yukl, Steven;Deeks, Steven;Wong, Joseph K.
通讯作者：
Wong, Joseph K.