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.

项目摘要/摘要 二十年前，有效治疗艾滋病毒的治疗方法，艾滋病毒感染的成年人的寿命 高资源环境已经增加到十年来未感染的人。但是，如果治疗是 由于持续和重新激活的病毒，停止病毒通常在血液中反弹至预处理水平 来自“艾滋病毒水库”。已经熟了适合数百万受感染个体的治疗疗法， 包括使用热疫苗的策略，化学疗法与干细胞移植，嵌合 急性感染期间，抗原受体细胞，基因疗法，细胞因子和抗逆转录病毒疗法。而很多 其中有减少了艾滋病毒储量，在一种情况下可能已经治愈了艾滋病毒感染，更好地理解了 需要建立有效，安全和 经济治疗。围产期感染儿童的HIV水库主要在感染初期建立 当他们的免疫系统具有耐受性以促进健康的妊娠时，共生后定植 细菌和食物的耐受性。我们建议检查四种可能有助于维持的机制 艾滋病毒水库并比较儿童与成人中每个人的贡献。我们假设两个 机制将针对儿童特定：（1）由于“围产期”感染（在子宫内或 生命的早期）当免疫对非自身抗原的免疫耐受性在内 （NIMA）和对食物的口服耐受性； （2）对HIV产生的“交叉免疫耐受性” 如同种异体移植所观察到的，孕产妇微思维（MMC）的水平升高。15在成人和儿童中， 我们假设通过（3）通过HIV整合对基因表达的调节来维持HIV储量 Treg的基因，促进这些细胞存活和/或通过抗病毒功能降低对其他细胞的生存 感染细胞； （4）由于细菌易位引起的肠道T-螺旋杆（Th）17个细胞的持续损失 促炎性细胞因子有利于Treg的发展和持久性而不是有效的抗病毒 CD4+ T细胞帮助。通过对从已知的南非儿童收集的标本的研究 我们将艾滋病毒收购，他们的母亲和未感染的对照，我们将测量每一个的参数 这些机制可以深入了解这些机制在维持感染性HIV储藏中的作用。 关于这四种机制在儿童与成年人中的相对贡献所获得的知识 应指出与我们可以在非人类隐私（NHP）中测试的儿童最相关的机制， 制定针对儿童确定的独特机制量身定制的干预措施的目的。