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.

抽象的 自从有效的HIV治疗可用以来的二十年中，艾滋病毒感染的成年人的寿命 资源设置已增加到未感染的个人十年之内。然而，抗逆转录病毒 治疗（ART）的恢复健康状况不足，如果治疗是停产的病毒，通常会反弹至 预处理水平由于持续性和重新激活而引起的。正在寻求治疗疗法， 包括热真空，化学疗法与干细胞移植，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倡议 急性感染。尽管其中一些方法减少了传染病的“储层”，其中一项 病例可能已经治愈了HIV感染，对HIV持续性的机制有更好的理解是 需要开发有效，安全和经济的治疗方法。艾滋病毒水库主要建立在早期 感染，当它们在艺术期间的衰败和构图变化时，维持水库的机制 仅部分知道。我们假设艾滋病毒水库是通过以下方式维护的：（1） 调节基因表达以促进这些细胞的存活，使感染的细胞能够通过增殖持续 或潜伏期； （2）由于T调节细胞失调，HIV特异性免疫复杂因素耗尽 源自病毒的整合； （3）表观遗传标记反映了病毒DNA的表达，允许 被感染的细胞持续存在，因为原病毒的“深”潜伏期。我们建议研究探讨这些作用 使用从独特的比利时收集的标本来维持艾滋病毒库的机制 在艺术抑制期间以及期间和之后采样的长期感染的个体队列 分析治疗中断（ATI）。这项研究的样品包括血液，脑脊髓液，骨髓， 支气管肺泡灌洗液，淋巴结，十二指肠，回肠和结肠。从 拟议的研究应指出可以测试的介入策略，并有可能有助于 制定干预以治愈艾滋病毒感染的目标。

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

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

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