Mechanisms controlling the persistence of infectious HIV reservoirs in children

项目摘要/摘要 20年前，有效的艾滋病毒治疗方法问世，中国感染艾滋病毒的成年人的寿命 高资源环境已增加到未感染患者的十年内。然而，如果治疗是 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到治疗前的水平 从“HIV水库”来的。人们一直在寻找适用于数百万感染者的根治疗法， 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、基因治疗、细胞因子和抗逆转录病毒治疗。虽然很多人 其中减少了艾滋病毒的储存，在一个病例中可能治愈了艾滋病毒感染，更好地了解了 开发一种有效的、安全的和 经济实惠的治疗方法。围产期感染儿童的艾滋病毒储备库主要是在感染早期建立的。 当他们的免疫系统是耐受性的，以促进健康的妊娠，出生后的定居与共生 细菌和食物的耐受性。我们建议审查四种可能有助于维持 并比较每种病毒在儿童和成人中的贡献。我们假设有两个 机制将针对儿童：(1)艾滋病毒的免疫耐受性，由于“围产期”感染(宫内或 生命的最初几周)对包括非遗传母体抗原在内的非自身抗原产生免疫耐受 (2)对艾滋病毒产生的“交叉免疫耐受”； 在同种异体移植中观察到的母体微嵌合体(MMC)水平增加。15成人和儿童， 我们假设HIV储存库是通过(3)HIV整合对基因表达的调节来维持的 促进这些细胞存活的Treg基因，和/或通过损害其他细胞的抗病毒功能 感染的细胞；以及(4)由于细菌易位引起的肠道T辅助细胞(Th)17细胞的持续丢失 促炎细胞因子有利于Treg的发展和持续，而不是有效的抗病毒药物 CD4+T细胞的帮助。通过对预期从南非儿童那里收集的样本的研究，已知 有围产期感染艾滋病毒的人，他们的母亲和未感染的对照，我们将测量每个参数 这些机制有助于深入了解这些机制在维持艾滋病毒感染性宿主方面的作用。 获得的关于这四种机制对儿童和成人的相对贡献的知识 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， 为儿童确定的独特机制制定干预措施的目标。

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.