Mechanisms controlling the persistence of infectious HIV reservoirs in children

控制儿童感染性艾滋病毒储存库持续存在的机制

• 批准号: 10224286
• 负责人: Lisa M Frenkel
• 金额: $ 56.42万
• 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: 2017-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224286
• 关键词: AIDS prevention; Address; Adherence; Adjuvant; Adult; Adult Children; Allografting; Anti-Retroviral Agents; Antigens; Antiviral Agents; Bacterial Translocation; Biological Markers; Biological Response Modifiers; Blood; Breast Feeding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Proliferation; Cell Survival; Cells; Child; Childhood; Clone Cells; Defective Viruses; Detection; Development; Food; Fostering; Frequencies; Gene Expression; Genes; Goals; HIV; HIV Infections; Immune; Immune Tolerance; Immune response; Immune signaling; Immune system; Immunologic Markers; Immunotherapy; Impairment; Individual; Infection; Inflammatory; Intervention; Knowledge; Life; Longevity; Measures; Mediating; Methods; Microchimerism; Mother-to-child HIV transmission; Mothers; Pathway interactions; Perinatal; Perinatal Infection; Population; Pregnancy; Preparation; Primates; Proliferating; Provirus Integration; Proviruses; Publishing; Receptor Cell; Regulatory T-Lymphocyte; Research Personnel; Resources; Role; Scientist; Serum; Sexual Partners; Signal Transduction; South African; Specimen; Stem cell transplant; Suspensions; T cell response; Testing; Therapeutic Uses; Time; Transcript; Treatment Effectiveness; Variant; Viral; Viral Antigens; Virus; acute infection; antiretroviral therapy; base; cancer cell; chemotherapy; chimeric antigen receptor; commensal bacteria; curative treatments; cytokine; cytokine therapy; design; effective therapy; exhaustion; experience; gene therapy; in utero; infancy; innovation; insight; integration site; microorganism; monocyte; nonhuman primate; novel; oral tolerance; perinatal HIV; pill; postnatal colonization; promoter; prospective; sexually transmitted virus; therapeutic vaccine; transcriptome; transcriptome sequencing; virus host interaction

Project Summary/Abstract Twenty years ago effective treatments for HIV became available, and the lifespan of HIV-infected adults in high-resource settings has increased to within a decade of uninfected individuals. However, if therapy is stopped virus generally rebounds in the blood to pretreatment levels, due to viruses that persist and reactivate from the “HIV Reservoir”. Curative therapies suitable for the millions of infected individuals have been sought, including strategies using therapeutic vaccines, chemotherapies paired with stem-cell transplant, chimeric antigen receptor cells, gene therapies, cytokines and antiretroviral therapy during acute infection. While many of these have reduced the HIV reservoir and in one case may have cured HIV infection, a better understanding of the mechanisms that allow persistence of the reservoir are needed to develop an effective, safe and economical cure. The HIV reservoir of perinatally infected children are primarily established early in infection when their immune system is tolerogenic to foster a healthy gestation, postnatal colonization with commensal bacteria and tolerance of foods. We propose to examine four mechanisms that could contribute to sustaining the HIV reservoirs and compare the contribution of each in children versus adults. We hypothesize that two mechanisms will be specific to children: (1) immune tolerance of HIV, due to “perinatal” infection (in utero or the early weeks of life) when immune tolerance to non-self antigens including non-inherited maternal antigens (NIMA) and oral tolerance to foods are established; and (2) “cross immune tolerance” to HIV generated by increased levels of maternal microchimerism (MMc), as observed with allografts.15 In both adults and children, we hypothesize that the HIV reservoir is maintained by (3) modulation of gene expression by HIV integration in genes of Treg that promote survival of these cells, and/or through impairment of antiviral functions towards other infected cells; and (4) by the persistent loss of gut T-helper (Th)17 cells due to bacterial translocation eliciting pro-inflammatory cytokines that favor the development and persistence of Tregs instead of effective antiviral CD4+ T-cell help. Through studies of specimens collected prospectively from South African children known to have acquired HIV perinatally, their mothers and uninfected controls, we will measure parameters of each of these mechanisms to gain insight into the roles of these mechanisms in sustaining the infectious HIV reservoir. The knowledge gained regarding the relative contribution of these four mechanisms in children vs. adults should point to mechanisms most relevant to children that we could test in non-human primates (NHP), with the goal of developing interventions tailored to the unique mechanisms identified in children.

项目总结/摘要 20年前，艾滋病毒的有效治疗方法问世， 高资源环境已增加到未受感染者的十年内。如果治疗是 停止的病毒通常在血液中反弹到治疗前的水平，这是由于病毒持续存在并重新激活 从“艾滋病病毒库”已经寻求了适合于数百万受感染个体的治愈性疗法， 包括使用治疗性疫苗的策略，与干细胞移植配对的化疗，嵌合 急性感染期间的抗原受体细胞、基因疗法、细胞因子和抗逆转录病毒疗法。虽然许多 其中一些减少了艾滋病毒储存库，在一种情况下可能治愈了艾滋病毒感染， 的机制，使水库的持久性需要开发一个有效的，安全的， 经济治愈围产期感染儿童的HIV宿主主要在感染早期建立 当他们的免疫系统是耐受原性的，以促进健康的妊娠，出生后定植与寄生虫 细菌和食物的耐受性。我们建议审查四种机制， 艾滋病毒库，并比较儿童与成人中每种病毒的贡献。我们假设两个 机制将是特定于儿童：（1）免疫耐受的艾滋病毒，由于“围产期”感染（在子宫内或 当对非自身抗原包括非遗传的母体抗原的免疫耐受时 （2）对HIV产生的“交叉免疫耐受”， 母体微嵌合体（MMc）水平增加，如在同种异体移植物中观察到的。15在成人和儿童中， 我们假设HIV库是通过以下方式维持的：（3）HIV整合对基因表达的调节， Treg的基因，其促进这些细胞的存活，和/或通过损害针对其他细胞的抗病毒功能， 感染的细胞;和（4）由于细菌易位引起的肠道辅助性T细胞（Th）17细胞的持续丢失 促炎性细胞因子，有利于发展和持续的TcR，而不是有效的抗病毒 CD 4 + T细胞帮助。通过对从南非儿童身上收集的样本进行研究， 已获得艾滋病毒围产期，他们的母亲和未感染的控制，我们将测量参数的每一个 这些机制，以深入了解这些机制在维持感染性艾滋病毒水库的作用。 关于这四种机制在儿童与成人中的相对作用的知识 应该指出与儿童最相关的机制，我们可以在非人类灵长类动物（NHP）中进行测试， 制定针对儿童独特机制的干预措施的目标。