Immunity and HIV persistence in perinatal HIV infection

围产期 HIV 感染中的免疫和 HIV 持续性

• 批准号: 9302666
• 负责人: Savita Pahwa
• 金额: $ 63.84万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-25 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302666
• 关键词: 1 year old; AIDS/HIV problem; Adult; Affect; Age; Alpha Cell; Antibody Response; Antigens; B-Lymphocytes; Biological Assay; Biological Markers; Birth; Breast Feeding; CD8B1 gene; Cells; Child; Childhood; Clinical Trials; Cohort Studies; Collaborations; Color; DNA; Development; Disease Progression; Disease remission; Early treatment; Event; Flow Cytometry; Frequencies; Gene Expression Profile; Gene Targeting; Genetic Transcription; Goals; HIV; HIV Core Protein p24; HIV Infections; HIV-exposed uninfected infant; Helper-Inducer T-Lymphocyte; Home environment; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Markers; Immunologic Memory; Immunologics; Infant; Infection; Investigation; Knowledge; Lead; Life; Measles Vaccine; Measures; Memory; Memory B-Lymphocyte; Mississippi; Mother-to-child HIV transmission; Mozambique; Natural Immunity; Natural Killer Cells; Nature; Participant; Patients; Perinatal; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Plasma; Postpartum Period; Prophylactic treatment; RNA; Regulatory T-Lymphocyte; Research; Resources; Role; Rome; Serologic tests; Sorting - Cell Movement; Structure of germinal center of lymph node; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Tetanus; Therapeutic; Time; Vaccination; Vaccines; Vertical Disease Transmission; Viral; Viral reservoir; Virus; Work; aged; antiretroviral therapy; biomarker development; cohort; combat; digital; genetic signature; immune activation; immune checkpoint; immune function; in utero; indexing; infancy; innovation; insight; lymph nodes; memory CD4 T lymphocyte; monocyte; novel; peripheral blood; permissiveness; phenotypic biomarker; predictive signature; prospective; tool; transcriptome sequencing; transcriptomics; vaccine response

Advances in maternal-infant HIV prophylaxis with antiretroviral therapy (ART) have dramatically reduced mother to child transmission (MTCT), but yearly, >200,000 new vertical HIV infections (HIV+) occur, predominantly in resource poor nations. With potent early ART initiation, HIV-infected (HIV+) infants can survive into adulthood. The role and nature of immune mechanisms that are important for HIV reservoir establishment and mechanisms of HIV persistence in HIV+ infants on ART are poorly understood and may differ in infants compared to adults. HIV infection stimulates an immune response that can be protective and have detrimental effects as well. The infant immune system undergoes dynamic developmental changes and is also challenged by vaccines to stimulate immunologic memory. T follicular helper cells (Tfh) are a unique subset of CD4 TCM cells that home to germinal centers (GC) in lymph nodes (LN) and facilitates antibody responses of B cells following vaccination, and this subset has been demonstrated in adults as a major HIV reservoir. We hypothesize that establishment of HIV reservoirs and HIV persistence in infancy are influenced by host immune response, timing of ART initiation and events such as childhood immunizations that stimulate immunologic memory. This proposal will perform investigations to assess latent and active reservoirs in peripheral blood in the context of a developing immune system prospectively in HIV+ infants starting ART at age <2 mo. in Maputo, Mozambique. Peripheral Tfh (pTfh), which are CD4 TCM subset with partial phenotypic and functional similarity to Tfh in LN will be investigated in infants given childhood vaccines. An older-aged HIV+ Rome cohort, (age 5y-18y) who started ART within age <1 year, either early (<6mo) or late (7-12mo) and remained consistently aviremic will provide complementary information about immunity and reservoirs in early versus late treated children after periods of durable viral control on ART. State-of-art tools including 15 color flow cytometry, RNA Sequencing, Fluidigm BioMark platform for transcriptomics of fractionated cells and droplet digital PCR for HIV reservoir are among techniques to be used for three specific aims: 1. To investigate immunologic biomarkers of HIV reservoirs pre-and post-ART in HIV+ infants starting ART at age <2 mo. and in older- aged children who started ART at different times <1 year of age. 2. To investigate the effect of childhood vaccinations on HIV reservoirs in HIV infected infants with early ART initiation and to evaluate their vaccine responses in comparison with EUI infants; 3. To investigate gene signatures in antigen-stimulated memory T cells including pTfh post-vaccination to ascertain the relationship between vaccine responses and HIV reservoirs. The proposed studies could provide insights that build new hypotheses, develop biomarkers of HIV reservoirs for selecting patients best suited for “cure” related clinical trials, and lead to innovative therapeutic strategies for eradication of active and latent HIV reservoirs for durable HIV remission.

用抗逆转录病毒疗法(ART)预防母婴艾滋病毒的进展已经大大减少。 母婴传播(MTCT)，但每年发生20万新的垂直艾滋病毒感染(HIV+)， 主要是在资源贫乏的国家。通过有效的早期抗逆转录病毒治疗，艾滋病毒感染(HIV+)婴儿可以 活到成年。免疫机制在HIV宿主中的重要作用和性质 在接受抗逆转录病毒治疗的HIV阳性婴儿中，HIV持续存在的建立和机制尚不清楚，可能 与成人相比，婴儿的差异很大。HIV感染刺激一种免疫反应，这种免疫反应可以起到保护性和 也有有害的影响。婴儿免疫系统经历动态发育变化 还面临着疫苗的挑战，以刺激免疫记忆。T滤泡辅助细胞(TFH)是一种 唯一的CD4中医细胞亚群，位于淋巴(LN)的生发中心(GC)，有助于 疫苗接种后B细胞的抗体反应，这一亚群已在成人中被证实为 主要的艾滋病毒携带者。我们假设HIV储备库的建立和HIV在 婴儿期受宿主免疫反应、开始抗逆转录病毒治疗的时间和事件的影响，如 刺激免疫记忆的儿童免疫接种。这项建议将执行 在发展的背景下评估外周血中潜在和活跃的储存库的调查 预期HIV+婴儿在2个月开始抗逆转录病毒治疗的免疫系统。在莫桑比克的马普托。 外周Tfh(PTfh)，这是与LN Tfh有部分表型和功能相似的CD4中医亚群 将在接种儿童疫苗的婴儿中进行调查。老年艾滋病毒+罗马队列(5岁至18岁) 在1岁内开始学习艺术，无论是早(6个月)还是晚(7-12个月)，并保持一贯的狂热意志 提供有关早期和晚期接受治疗的儿童的免疫力和宿主的补充信息 对ART进行持续病毒控制的时期。最先进的工具包括15色流式细胞仪，RNA 测序，用于分离细胞转录的Fluidigm BioMark平台和Droplet数字聚合酶链式反应 HIV储存库是用于三个特定目的的技术之一：1.调查免疫学 艾滋病病毒携带者在2个月开始接受抗逆转录病毒治疗的婴儿接受抗逆转录病毒治疗前后的生物标志物。而在更老的时候- 年龄较大的儿童，在不同的时间和1岁开始艺术。2.调查童年的影响 早期抗逆转录病毒治疗的HIV感染婴儿的HIV疫苗接种及其疫苗评价 与EUI婴儿的反应比较；3.研究抗原刺激记忆中的基因特征 包括pTfh在内的T细胞在疫苗接种后确定疫苗反应与HIV之间的关系 水库。拟议的研究可以提供见解，建立新的假设，开发生物标记物 艾滋病毒储存库，用于选择最适合进行相关临床试验的患者，并引领创新 根除艾滋病毒活动性和潜伏性宿主的治疗战略，以实现艾滋病毒的持久缓解。