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.

项目概要/摘要 二十年前，艾滋病毒的有效治疗方法问世，艾滋病毒感染者的寿命缩短了 然而，如果治疗有效的话，资源丰富的地区已增加到十年内未感染的人数。 由于病毒持续存在并重新激活，停止的病毒通常会在血液中反弹至治疗前的水平 从“艾滋病病毒库”中寻找适合数百万感染者的治疗方法， 包括使用治疗性疫苗、化疗与干细胞移植、嵌合疗法相结合的策略 急性感染期间的抗原受体细胞、基因治疗、细胞因子和抗逆转录病毒治疗等多种。 其中一些已经减少了艾滋病毒储存库，并且在一个案例中可能治愈了艾滋病毒感染，更好地了解 需要研究允许储存库持续存在的机制，以开发有效、安全和 围产期感染儿童的艾滋病毒储存库主要在感染早期就已建立。 当他们的免疫系统具有耐受性以促进健康妊娠时，产后共生定植 我们建议研究四种可能有助于维持的机制。 我们研究了艾滋病毒储存库，并比较了儿童和成人中每种病毒的贡献。 机制将针对儿童：(1) 由于“围产期”感染（在子宫内或子宫内）对艾滋病毒的免疫耐受 生命的最初几周）对非自身抗原（包括非遗传性母体抗原）产生免疫耐受 (NIMA) 和对食物的口服耐受性已建立；(2) 对 HIV 产生的“交叉免疫耐受性”； 正如同种异体移植物所观察到的，母体微嵌合体 (MMc) 水平增加。 15 在成人和儿童中， 我们认为，HIV 储存库是通过 (3) HIV 整合调节基因表达来维持的。 Treg 基因促进这些细胞的存活，和/或通过损害其他细胞的抗病毒功能 受感染的细胞；(4) 由于细菌易位导致肠道辅助性 T (Th)17 细胞持续丢失 有利于 Tregs 发育和持续存在的促炎细胞因子，而不是有效的抗病毒药物 CD4+ T 细胞的帮助是通过对从已知的南非儿童中前瞻性收集的样本进行的研究。 围产期感染艾滋病毒的人、他们的母亲和未感染的对照者，我们将测量每个人的参数 这些机制可以深入了解这些机制在维持传染性艾滋病毒储存库中的作用。 关于这四种机制在儿童与成人中的相对贡献的知识 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，其中 制定针对儿童独特机制的干预措施的目标。