Defining HIV reservoirs that rebound following suspension of ART

定义暂停 ART 后反弹的 HIV 病毒库

• 批准号: 9976441
• 负责人: Lisa M Frenkel
• 金额: $ 78.58万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-17 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976441
• 关键词: Adult; Anatomy; Anti-Inflammatory Agents; Antibodies; Biological; Blood; Bone Marrow; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cardiovascular system; Cell Proliferation; Cell Survival; Cells; Cerebrospinal Fluid; Chronic; Clone Cells; Colon; Communities; DNA; Defective Viruses; Disease; Duodenum; Epigenetic Process; FOXP3 gene; Frequencies; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Goals; HIV; HIV Infections; HIV-1; Health; Homeostasis; Immune; Immune response; Individual; Infection; Interruption; Intervention; Knowledge; Link; Liquid substance; Longevity; Medical; Methods; Methylation; Mutation; Outcome; Pathway interactions; Phenotype; Phylogenetic Analysis; Plasma; Population; Proliferating; Prophylactic treatment; Provirus Integration; Proviruses; Publishing; Regulatory T-Lymphocyte; Residual state; Resources; Role; Sampling; Sampling Studies; Source; Specimen; Stem cell transplant; Suspensions; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tissues; Transforming Growth Factor beta; Viral; Viral reservoir; Viremia; Virus; acute infection; antiretroviral therapy; base; cancer risk; chemotherapy; chimeric antigen receptor T cells; cohort; curative treatments; cytokine; effective therapy; exhaust; exhaustion; falls; gene cloning; gene therapy; ileum; immune function; integration site; lymph nodes; novel; particle; pill; programmed cell death protein 1; prospective; therapeutic vaccine; viral rebound

ABSTRACT In the twenty years since effective HIV treatments became available, the lifespan of HIV-infected adults in high- resource settings has increased to within a decade of uninfected individuals. Nevertheless, antiretroviral treatments (ART) fall short in restoring health, and if therapy is discontinued virus usually rebounds to pretreatment levels due the persistence and reactivation of proviruses. Curative therapies are being sought, including therapeutic vaccines, chemotherapies paired with stem-cell transplant, chimeric antigen receptor T cells, neutralizing and immune modulating antibodies, gene therapies, cytokines and initiation of ART during acute infection. While some of these approaches have reduced the “reservoirs” of infectious viruses and in one case may have cured HIV infection, a better understanding of the mechanisms underlying HIV persistence is needed to develop an effective, safe and economical cure. HIV reservoirs are primarily established early in infection, and while they decay and change in composition during ART, the mechanisms that sustain reservoirs are only partially known. We hypothesize that HIV reservoirs are maintained by: (1) Integrated proviruses that modulate gene expression to promote survival of these cells, allowing infected cells to persist by proliferation or latency; (2) HIV-specific immune responses become exhausted due to dysregulation of T-regulatory cells resulting from provirus integration; and (3) Epigenetic marks repress expression of proviral DNA, allowing infected cells to persist due to “deep” latency of proviruses. We propose studies to explore the role of these mechanisms in sustaining HIV reservoirs using specimens collected prospectively from a unique Belgian cohort of chronically infected individuals sampled during ART-suppression as well as during and after an analytical treatment interruption (ATI). Samples for this study include blood, cerebral spinal fluid, bone marrow, bronchioalveolar lavage fluid, lymph node, duodenum, ileum, and colon. The knowledge gained from the proposed studies should point to interventional strategies that could be tested and potentially contribute to the goal of developing an intervention to cure HIV infection.

抽象的 自有效的艾滋病毒治疗出现以来的二十年里，艾滋病毒感染者的寿命在高 资源设置已增加到十年内未受感染的个体。尽管如此，抗逆转录病毒 治疗（ART）不足以恢复健康，如果停止治疗，病毒通常会反弹到 由于原病毒的持续存在和重新激活而导致的预处理水平。正在寻求治疗方法， 包括治疗性疫苗、化疗联合干细胞移植、嵌合抗原受体 T 细胞、中和和免疫调节抗体、基因疗法、细胞因子和 ART 的启动 急性感染。虽然其中一些方法减少了传染性病毒的“储存库”，并且在一种方法中 病例可能已经治愈了艾滋病毒感染，更好地了解艾滋病毒持续存在的机制是 需要开发一种有效、安全和经济的治疗方法。 HIV 储存库主要在早期建立 感染，虽然它们在 ART 期间腐烂和成分发生变化，但维持储存库的机制 仅部分已知。我们假设 HIV 储存库是通过以下方式维持的： (1) 整合的原病毒 调节基因表达以促进这些细胞的存活，使受感染的细胞能够通过增殖而持续存在 或延迟； (2) 由于 T 调节细胞失调，HIV 特异性免疫反应变得疲惫不堪 由原病毒整合产生； (3) 表观遗传标记抑制原病毒 DNA 的表达，从而允许 由于原病毒的“深度”潜伏期，受感染的细胞得以持续存在。我们提出研究来探索这些的作用 使用从独特的比利时人中前瞻性收集的样本来维持艾滋病毒储存库的机制 在 ART 抑制期间以及抗逆转录病毒疗法期间和之后采样的慢性感染个体队列 分析治疗中断（ATI）。本研究的样本包括血液、脑脊液、骨髓、 支气管肺泡灌洗液、淋巴结、十二指肠、回肠和结肠。从中获得的知识 拟议的研究应指出可以测试并可能有助于治疗的干预策略 开发治疗艾滋病毒感染的干预措施的目标。