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）： HIV-1在患者中持续存在，尽管抗逆转录病毒疗法（ART）进行了多年的抑制性治疗，并在治疗中断时导致疾病复发。治疗根除的一个主要障碍是潜伏感染的CD 4 + T细胞的储库。这些潜伏感染的细胞是否引起低水平的持续复制或间歇性激活并产生病毒是有争议的，但这种病毒持续存在可能有助于持续的免疫病理学效应，包括不完全的T细胞恢复和整体免疫激活，这些免疫激活与HIV相关的心血管、肾脏和肝脏疾病有关，即使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T细胞活化的一些标志物，但来自HIV感染患者的T细胞也表现出T细胞耗竭或耐受的标志物，这可能是针对HIV-1的免疫应答不足的基础。我们在上一个资助周期的工作表明，潜伏病毒库在体内的组成可能是异质的，病毒潜伏的分子机制可能是复杂的。我们发现，尽管T细胞活化水平很高，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表达减弱的一个统一机制可能是似乎伴随HIV感染的T细胞耗竭。我们的初步数据表明，矛盾的是，在ART成功抑制病毒后，表达CTLA-4（T细胞无反应性的标志物）的细胞比例增加。在目前的建议中，我们将调查从患者开始治疗慢性HIV感染的病毒细胞库的演变，通过检查个人的CD 4群体的基础上存在或不存在的标志物的激活和无反应性。我们将测试新的假设，即作为慢性HIV感染的副产品获得的耐受性，减弱病毒表达，并引起抑制治疗期间大量潜伏HIV感染细胞的矛盾保留。我们将确定HIV LTR的表观遗传修饰是否与T细胞活化相关基因启动子的表观遗传修饰一致。最后，我们将研究旨在从潜伏期重新激活HIV或逆转T细胞无反应性的药物对抑制治疗患者T细胞病毒表达的影响，以形成未来干预措施的基础，以清除潜伏的水库。 公共卫生相关性： 艾滋病毒感染了4万名美国退伍军人，尽管有有效的抗病毒药物可以抑制艾滋病毒感染，但在所有需要终身治疗的患者中仍然存在少量病毒。这种病毒残留物和/或我们用来治疗它的药物也可能导致心脏病发作，中风，肾脏和肝脏疾病以及癌症增加。我们需要更好地了解艾滋病毒是如何隐藏在体内的，以及如何才能完全消除它。这项拟议中的研究将更准确地确定哪些细胞在庇护病毒，以及为什么它们能够这样做。我们还将测试一些新药是否能够迫使艾滋病毒从这些细胞中消失。这些研究可能会指出新的干预措施来消除（根除）这些持续感染的细胞。