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

HIV 潜伏期的药物基因组学研究：PD-1 信号传导的作用

• 批准号: 8789728
• 负责人: Sulggi Angela Lee
• 金额: $ 18.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789728
• 关键词: AIDS/HIV problem; Acute; Address; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apoptosis; Area; Bioinformatics; Blood; CCR5 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Clinical; Clinical Trials; DNA; Data; Defect; Disease; Disease Progression; Epidemiologic Studies; Evaluation; Exhibits; FOXO3A gene; Fluorescence; Flushing; Funding; Future; Gagging; Gene Expression Regulation; Gene Mutation; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; HIV vaccine; Health; Hepatitis C; Hour; Immune System Diseases; Immune response; Immune system; Immunologics; Immunology; In Vitro; Individual; Infection; Inflammation; Integration Host Factors; Intervention; Kinetics; Life; Macaca mulatta; Malignant Neoplasms; Measures; Mediating; Memory; Mentors; Nucleic Acid Regulatory Sequences; PTPN11 gene; PTPN6 gene; Pathway interactions; Patients; Peripheral; Personal Communication; Persons; Pharmaceutical Preparations; Pharmacogenomics; Phase I Clinical Trials; Play; Process; Production; Proto-Oncogene Proteins c-akt; RNA Sequences; Relative (related person); Research; Research Personnel; Research Priority; Risk; Role; Sampling; Shapes; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Signaling Protein; Site; Sorting - Cell Movement; Staging; T cell response; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Time; Training; Transcript; United States National Institutes of Health; Viral; Virus; Work; antiretroviral therapy; base; career development; collaboratory; exome sequencing; genetic association; genome wide association study; human leukocyte antigen gene; immune activation; immune function; improved; in vivo; inhibitor/antagonist; mortality; nonhuman primate; novel; pathogen; protein activation; protein expression; research study; response; tumor

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.

艾滋病治愈已成为一个重要的研究重点。消灭艾滋病毒战略的一个关键挑战是“艾滋病毒库”，即尽管抗逆转录病毒治疗（ART），艾滋病毒仍然存在的细胞。目前正在进行研究，以了解艾滋病毒储存库是如何建立的，以及如何根除携带艾滋病毒的细胞。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，这些突变决定了(1)HIV储存库的大小和(2)对旨在从储存库中“冲洗”HIV的新药的反应。HIV病毒库大小的决定因素包括抗逆转录病毒治疗开始时的疾病阶段（急性感染与慢性感染的库大小较低）和宿主因素，如T细胞活化水平和T细胞功能。然而，这些因素只能解释HIV病毒库大小的一部分人与人之间的差异。由于宿主遗传（例如，HLA和CCR5基因的多态性）影响HIV在没有治疗的情况下复制的程度，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性将在塑造HIV储存库的大小和分布方面发挥作用。解决这一假设的实验将是Aim 1的重点。Aim 2的实验将评估宿主对抗程序性细胞死亡-1 （PD-1）抗体lambrolizumab药物反应的遗传预测因子。尽管终身抗逆转录病毒治疗能抑制病毒，但慢性艾滋病毒感染患者仍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。其中一个抑制过程是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，PD-1表达细胞似乎也富集了病毒。我们的合作者已经证明，用lambrolizumab阻断恒河猴体内的PD-1，会导致病毒从储存库释放的短暂增加，并改善免疫功能。鉴于PD-1被认为是HIV持续存在的原因，lambrolizumab的I期临床试验已经开发，计划于2014年开始。这种药物也在早期癌症试验中进行了研究，显示出良好的肿瘤反应率和很少的不良反应。从PD-1途径抑制剂的癌症和丙型肝炎试验中，一个一致而令人困惑的发现是宿主反应的二分性；患者对这种药物的反应要么很好，要么很弱。Aim 2的实验将评估宿主遗传学在对lambrolizumab的二分性反应中的作用，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。本次提案的实验相关工作将为我提供HIV免疫学和遗传学方面的重要培训，目标是为未来的HIV治疗研究做出贡献。