A pharmacogenomics study of HIV latency: the role of PD-1 signaling

描述：艾滋病毒的治愈已成为一个重要的研究重点。根除艾滋病毒战略中的一个关键挑战是“艾滋病毒储存库”，即尽管接受了抗逆转录病毒治疗(ART)，但艾滋病毒仍在其中的细胞。目前正在进行研究，以了解艾滋病毒宿主是如何建立的，以及携带艾滋病毒的细胞可能如何被根除。这项K23提案的实验将使用最先进的基因测序技术来发现潜在的宿主基因突变，这些突变决定(1)艾滋病毒储存库的大小和(2)对一种旨在将艾滋病毒从储存库中“冲出”的新药的反应。艾滋病毒储存库大小的决定因素包括ART启动时的疾病阶段(急性感染与慢性感染的储存库大小较低)和宿主因素，如T细胞激活水平和T细胞功能。然而，这些因素只能解释HIV储备库大小在人与人之间的一小部分变异性。由于宿主遗传学(例如，人类白细胞抗原和CCR5基因的多态)在缺乏治疗的情况下影响HIV复制的程度，我们假设在ART介导的病毒抑制过程中，一组独特的宿主遗传多态将在塑造HIV储存库的大小和分布方面发挥作用。针对这一假说的实验将是目标1的重点。目标2的实验将评估宿主遗传预测因子对抗程序性细胞死亡-1(PD-1)抗体lambrolizumab的药物反应。尽管用终生抗逆转录病毒疗法抑制病毒，但慢性艾滋病毒感染患者表现出持续的免疫功能障碍和炎症。宿主免疫系统试图通过上调抗炎过程来抑制有害的全身炎症。一个这样的抑制过程是PD-1信号通路。表达PD-1的T细胞功能较差，不能有效清除病原体。在HIV疾病中，表达PD-1的细胞似乎也富含病毒。我们的合作者已经证明，用lambrolizumab阻断恒河猴的PD-1，可以导致从宿主部位释放的病毒瞬时增加，并改善免疫功能。鉴于PD-1被认为是艾滋病毒持续存在的原因，已经开发了Lambrolizumab的I期临床试验，并计划于2014年开始。这种药物也已经在早期癌症试验中进行了研究，显示出良好的肿瘤应答率和很少的不良反应。在癌症和丙型肝炎的PD-1途径抑制剂试验中，一个一致而令人困惑的发现是宿主反应二分法；患者对该药物的反应要么很好，要么最低。AIM 2的实验将评估宿主遗传学在对Lambrolizumab的二分反应中的作用，而Aim 3的实验将更全面地评估Aim 2中确定的宿主反应中涉及的任何基因的作用。与本提案实验相关的工作将为我提供重要的HIV免疫学和遗传学方面的培训，目标是为未来的HIV治疗研究做出贡献。

DESCRIPTION: HIV cure has emerged as an important research priority. A key challenge in HIV eradication strategies is the "HIV reservoir," i.e., the cells in which HIV persists despite antiretroviral therapy (ART). Studies are now underway to understand how the HIV reservoir is established and how cells harboring HIV may be eradicated. The experiments of this K23 proposal will use state-of-the-art genetic sequencing techniques to discover potential host genetic mutations that determine (1) the HIV reservoir size and (2) the response to a novel drug aimed at "flushing out" HIV from reservoir sites. The determinants of HIV reservoir size include stage of disease at ART initiation (lower reservoir sizes with acute versus chronic infection) and host factors such as the level of T cell activation and T cell function. However, these factors onl explain a fraction of the person-to- person variability in HIV reservoir size. Since host genetics (e.g., polymorphisms in HLA and CCR5 genes) influence the degree to which HIV replicates in the absence of therapy, we hypothesize that a unique set of host genetic polymorphisms will play a role in shaping the size and distribution of the HIV reservoir during ART-mediated viral suppression. Experiments addressing this hypothesis will be the focus of Aim 1. The experiments of Aim 2 will evaluate host genetic predictors of drug response to an anti-programmed cell death-1 (PD-1) antibody, lambrolizumab. Despite viral suppression with life-long ART, chronically HIV-infected patients exhibit persistent immune dysfunction and inflammation. The host immune system attempts to dampen harmful systemic inflammation by upregulating anti-inflammatory processes. One such inhibitory process is the PD-1 signaling pathway. PD-1 expressing T cells are less functional and do not clear pathogens effectively. In HIV disease, PD-1 expressing cells also appear to be enriched for virus. Our collaborators have shown that blocking PD-1 in rhesus macaques with lambrolizumab, leads to a transient increase in virus released from reservoir sites as well as improved immune function. Given the putative role of PD-1 as a cause of HIV persistence, a Phase I clinical trial of lambrolizumab has been developed and is planned to begin in 2014. This drug has also been studied in early cancer trials, demonstrating good tumor response rates and few adverse effects. A consistent and perplexing finding from cancer and hepatitis C trials of PD-1 pathway inhibitors is the dichotomous host responses; patients either respond very well or minimally to the drug. The experiments of Aim 2 will evaluate the role of host genetics in the dichotomous response to lambrolizumab while those of Aim 3 will more completely evaluate the role of any genes implicated in the host responses identified in Aim 2. The work associated with the experiments of this proposal will provide me with important training in HIV immunology and genetics with the goal of contributing to future HIV cure research.