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: 9211649
• 负责人: Savita Pahwa
• 金额: $ 64.55万
• 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/9211649
• 关键词: 1 year old; AIDS/HIV problem; Adult; Affect; Age; Antibody Response; Antigens; Arecaceae; Arts; B-Lymphocytes; Biological Assay; Biological Markers; Birth; Breast Feeding; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Child; Childhood; Clinical Trials; Cohort Studies; Collaborations; Color; DNA; Development; Disease Progression; Disease remission; Drug Controls; 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 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; Plasma; Postpartum Period; Prophylactic treatment; RNA; RNA Sequences; Reaction Time; 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; base; biomarker development; cohort; combat; digital; genetic signature; immune activation; immune function; in utero; indexing; infancy; innovation; insight; lymph nodes; memory CD4 T lymphocyte; monocyte; novel; peripheral blood; phenotypic biomarker; predictive signature; tool; 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.

抗逆转录病毒疗法（ART）在母婴艾滋病毒预防方面的进展大大减少了 母婴传播（MTCT），但每年有> 200 000例新的纵向艾滋病毒感染（艾滋病毒+）发生， 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+）的婴儿可以 活到成年。对HIV宿主重要的免疫机制的作用和性质 对接受抗逆转录病毒治疗的艾滋病毒阳性婴儿中艾滋病毒持续存在的建立和机制知之甚少， 与成人相比，婴儿有所不同。HIV感染会刺激免疫反应， 也有不利影响。婴儿免疫系统经历动态的发育变化 并且还受到疫苗的挑战以刺激免疫记忆。滤泡辅助性T细胞（Tfh）是一种 CD 4 TCM细胞的独特亚群，其归巢于淋巴结（LN）中的生殖中心（GC），并促进 免疫接种后B细胞的抗体应答，并且该亚群已在成人中被证明是 主要的艾滋病病毒库。我们假设，建立艾滋病毒库和艾滋病毒的持久性， 婴儿期受宿主免疫应答、ART启动时间和诸如 儿童期免疫接种能刺激免疫记忆。该提案将执行 在发展中国家的背景下评估外周血中潜伏和活动储库的研究 在年龄<2个月时开始抗逆转录病毒治疗的HIV阳性婴儿中，在莫桑比克的马普托。 外周血Tfh（pTfh）是与LN患者Tfh具有部分表型和功能相似性的CD 4 Tcm亚群 将在接种儿童疫苗的婴儿中进行研究。一个老年HIV阳性罗马队列（5 - 18岁）， 在年龄<1岁内开始ART，早期（<6个月）或晚期（7- 12个月），并保持一致的aviremic意愿 提供关于免疫力和水库的补充信息，在早期与晚期治疗的儿童后， 最先进的工具，包括15色流式细胞术，RNA 测序，Fluidigm BioMark平台用于分级细胞的转录组学和液滴数字PCR， 艾滋病毒库是用于三个具体目标的技术之一：1。研究免疫学 在年龄<2个月时开始抗逆转录病毒治疗的艾滋病毒阳性婴儿中，抗逆转录病毒治疗前后艾滋病毒储库的生物标志物。在老年人中， 在不同时间开始抗逆转录病毒治疗的1岁以下儿童。2.为了调查童年对 在早期开始抗逆转录病毒治疗的艾滋病毒感染婴儿中接种艾滋病毒疫苗，并评估其疫苗 与EUI婴儿相比的反应; 3.研究抗原刺激记忆中的基因特征 接种后T细胞包括pTfh，以确定疫苗应答与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，开发生物标志物， 艾滋病病毒库选择患者最适合“治愈”相关的临床试验，并导致创新 根除活动性和潜伏性HIV宿主以实现持久HIV缓解的治疗策略。