The contribution of Tcell tolerance to latent HIV infection

T细胞耐受性对HIV潜伏感染的贡献

• 批准号: 8049265
• 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
• 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/8049265
• 关键词: Address; Aftercare; Antiviral Agents; Attenuated; Biological Assay; Blood; Blood Circulation; CD4 Positive T Lymphocytes; 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

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. PUBLIC HEALTH RELEVANCE: HIV infects 40,000 US Veterans and despite the availability of potent antiviral drugs that inhibit HIV infection, small amounts of virus remain in all patients on treatment requiring lifelong therapy. This virus remnant and/or the drugs we use to treat it may also be contributing to increases in heart attacks, strokes, kidney and liver disease and increases in cancer. We need to better understand how HIV is able to hide in the body and what can be done to completely eliminate it. This proposed study will determine more exactly what cells are sheltering the virus and why they are able to do so. We will also test whether some new drugs are able to force HIV out of hiding from these cells. These studies might point to new interventions for ridding (eradicating) these persistently infected cells.

描述（由申请人提供）： 尽管多年的抗逆转录病毒疗法（ART）抑制治疗，但HIV-1仍然存在于患者中，并在中断治疗时会导致疾病复发。消除治疗的一个主要障碍是潜在感染的CD4+ T细胞的储层。这些潜在感染的细胞是否会引起低水平的正在进行的复制或情景激活并产生病毒是有争议的，但是这种病毒持久性可能有助于持续的免疫病理学作用，包括不完整的T细胞恢复和与HIV相关的心血管，肾脏，肾脏，肾脏疾病中伴随的全球免疫激活，即使是在高度上进行的抗病，即使是高度疾病的抗病术语，甚至对那些人的疾病中的那些人也有效地静止。最近还认识到，尽管表达了一些T细胞激活的一些标记，但来自HIV感染患者的T细胞也表现出T细胞耗尽或耐受性的标志物，这可能是针对HIV-1的免疫反应不足。我们从前一个资金周期的工作表明，潜在病毒储存剂在体内的组成中可能是异质的，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，但肠道中的两个T细胞和血液中的T细胞表现出非常低的HIV表达水平。艾滋病毒衰减表达的一种统一机制可能是伴随HIV感染的T细胞疲劳。我们的初步数据表明，在成功抑制ART的病毒抑制后，矛盾的是，表达CTLA-4的细胞的比例（T-Cell Anergy的标记）增加了。在当前的提案中，我们将根据存在基于存在或不存在激活和不良标记的单个CD4种群来研究慢性HIV感染期间患者的细胞病毒库的演变。我们将检验一个新的假设，即耐受性作为慢性HIV感染的副产品，减轻病毒表达，并导致抑制性治疗期间患有潜在HIV感染的大量细胞的矛盾保留。我们将确定HIV LTR的表观遗传修饰是否与与T细胞激活相关的基因启动子的表观遗传学修饰一致。最后，我们将研究旨在从潜伏期重新激活HIV的药物的作用，或者从抑制治疗中获得的T细胞反向T细胞表达对病毒表达，以构成未来干预措施以清除潜在储层的基础。 公共卫生相关性： 艾滋病毒感染了40,000名美国退伍军人，尽管有抑制艾滋病毒感染的有效抗病毒药物，但在所有需要终身治疗的治疗中，所有患者仍有少量病毒。这种病毒残留和/或我们用来治疗的药物也可能导致心脏病发作，中风，肾脏和肝病的增加以及癌症的增加。我们需要更好地了解艾滋病毒如何藏在体内，以及如何完全消除它。这项拟议的研究将更准确地确定哪些细胞掩盖了病毒，以及为什么它们能够这样做。我们还将测试某些新药是否能够迫使HIV远离这些细胞。这些研究可能指出了这些持续感染的细胞的新干预措施（消除）。