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: 10220678
• 负责人: Lisa M Frenkel
• 金额: $ 72.58万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220678
• 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; epigenetic silencing; 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.

摘要 自有效的艾滋病毒治疗方法问世以来的20年里，感染艾滋病毒的成年人的寿命在 资源设置已增加到未感染患者的十年内。然而，抗逆转录病毒 治疗(ART)不能恢复健康，如果停止治疗，病毒通常会反弹到 预处理水平是由于前病毒的持续和重新激活所致。人们正在寻求根治疗法， 包括治疗性疫苗、与干细胞移植配对的化疗、嵌合抗原受体T 细胞，中和抗体和免疫调节抗体，基因治疗，细胞因子和启动抗逆转录病毒治疗 急性感染。虽然这些方法中的一些已经减少了传染性病毒的“蓄水池”，但在一个 一例可能治愈了艾滋病毒感染，更好地理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。艾滋病毒宿主最初是在 感染，当它们在ART过程中腐烂和成分变化时，维持储层的机制 只有部分人知道。我们假设艾滋病毒宿主是通过以下方式维持的：(1)综合方案 调节基因表达以促进这些细胞的存活，使受感染的细胞通过增殖而持续存在 或潜伏期；(2)由于T调节细胞调节失调，HIV特异性免疫反应变得疲惫 以及(3)表观遗传标记抑制前病毒DNA的表达，允许 由于前病毒的“深”潜伏期，被感染的细胞持续存在。我们建议进行研究，以探索这些因素的作用 利用从一个独特的比利时人身上收集的样本维持艾滋病毒储存库的机制 在ART抑制期间以及在ART期间和之后抽样的慢性感染者的队列 分析处理中断(ATI)。这项研究的样本包括血液，脑脊液，骨髓， 细支气管肺泡灌洗液、淋巴结、十二指肠、回肠和结肠。从调查中获得的知识 拟议的研究应该指出可以测试的干预策略，并可能有助于 开发一种治疗艾滋病毒感染的干预措施的目标。

项目成果

Chromatin changes trigger laminin genes dysregulation in aging kidneys.

• DOI: 10.18632/aging.101453
• 发表时间: 2018-05-29
• 期刊: Aging
• 作者: Denisenko O;Mar D;Trawczynski M;Bomsztyk K
• 通讯作者: Bomsztyk K

HIV-PULSE: a long-read sequencing assay for high-throughput near full-length HIV-1 proviral genome characterization.

• DOI: 10.1093/nar/gkad790
• 发表时间: 2023-11-10
• 期刊: Nucleic acids research
• 影响因子: 14.9

Follicular CD4 T Helper Cells As a Major HIV Reservoir Compartment: A Molecular Perspective.

• DOI: 10.3389/fimmu.2018.00895
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Aid M;Dupuy FP;Moysi E;Moir S;Haddad EK;Estes JD;Sekaly RP;Petrovas C;Ribeiro SP
• 通讯作者: Ribeiro SP