The contribution of Tcell tolerance to latent HIV infection

描述(由申请人提供)： 尽管使用抗逆转录病毒疗法(ART)进行了多年的抑制治疗，但艾滋病毒-1仍在患者中持续存在，并在治疗中断时导致疾病复发。根除治疗的一个主要障碍是潜伏感染的CD4+T细胞的储存库。这些潜伏感染的细胞是否会导致低水平的持续复制或偶尔激活并产生病毒仍存在争议，但这种病毒持久性可能导致持续的免疫病理效应，包括T细胞不完全恢复和全球免疫激活，这与HIV相关的心血管、肾脏和肝脏疾病有关，即使在接受高效抗逆转录病毒治疗(HAART)的患者中也是如此。最近也认识到，尽管HIV感染者的T细胞表达一些T细胞激活的标志，但也表现出T细胞耗竭或耐受的标志，这可能是导致对HIV-1免疫反应不足的原因。我们从上一个资金周期的工作表明，潜伏的病毒库在体内的组成可能是不同的，潜在的病毒潜伏的分子机制可能是复杂的。我们发现，肠道和血液中的T细胞都表现出非常低的HIV表达水平，尽管T细胞处于高水平的激活状态。HIV表达减弱的一个统一机制可能是伴随着HIV感染而出现的T细胞耗尽。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的细胞比例增加，CTLA-4是T细胞无能的标志。在目前的提案中，我们将根据激活和无能的标记的存在或不存在，通过检查单个CD4群体，来研究慢性HIV感染期间开始治疗的患者的细胞毒库的演变。我们将检验这一新的假设，即作为慢性艾滋病毒感染的副产品而获得的耐受性，会减弱病毒的表达，并在抑制治疗期间引起大量潜在艾滋病毒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细胞激活相关基因启动子的表观遗传修饰一致。最后，我们将检查旨在从潜伏期重新激活HIV的药物或逆转T细胞无能的药物对从接受抑制治疗的患者获得的T细胞中病毒表达的影响，以便为未来的干预措施清除潜伏库奠定基础。

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.