Immunity and HIV persistence in perinatal HIV infection

围产期 HIV 感染中的免疫和 HIV 持续性

基本信息

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
项目类别：
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

项目摘要

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.

通过抗逆转录病毒疗法（ART）预防母婴艾滋病毒的进展已大大减少母婴传播 (MTCT)，但每年都会发生超过 200,000 例新的垂直艾滋病毒感染 (HIV+)，主要是在资源匮乏的国家，通过有效的早期抗逆转录病毒治疗，感染艾滋病毒（HIV+）的婴儿可以存活到成年期的免疫机制的作用和性质对于艾滋病毒储存库很重要。接受 ART 治疗的 HIV+ 婴儿中 HIV 持续存在的建立和机制知之甚少，可能与成人相比，婴儿感染艾滋病毒会刺激免疫反应，从而发挥保护作用。婴儿免疫系统也会经历动态的发育变化。并且还受到刺激免疫记忆的疫苗的挑战。 CD4 TCM 细胞的独特子集，位于淋巴结 (LN) 中的生发中心 (GC)，并促进接种疫苗后 B 细胞的抗体反应，并且该子集已在成人中被证明是我们率先建立了艾滋病毒储存库和艾滋病毒持久性。婴儿期受到宿主免疫反应、ART开始时间和事件的影响，例如刺激免疫记忆的儿童免疫接种将发挥作用。在发展中的背景下评估外周血中潜在和活跃储库的研究在莫桑比克马普托，对 2 个月以下开始接受 ART 的 HIV + 婴儿的免疫系统进行前瞻性研究。外周 Tfh (pTfh)，是 CD4 TCM 子集，与 LN 中的 Tfh 具有部分表型和功能相似性将在接种儿童疫苗的老年 HIV 阳性罗马队列（5 岁至 18 岁）中进行研究。在<1岁之内开始ART，无论是早期（<6个月）还是晚期（7-12个月），并且始终保持无病毒血症意愿提供有关早期和晚期治疗儿童的免疫和储存库的补充信息 ART 的持久病毒控制期最先进的工具，包括 15 色流式细胞术、RNA。测序、用于分级细胞转录组学的 Fluidigm BioMark 平台和微滴数字 PCR HIV 储存库技术可用于三个具体目标： 1. 研究免疫学在小于 2 个月开始接受 ART 的 HIV + 婴儿和年龄较大的婴儿中，ART 前后 HIV 储存库的生物标志物。在不同时间开始 ART 的年龄 <1 岁的儿童 2. 调查童年时期的影响。对早期开始接受抗逆转录病毒治疗的艾滋病毒感染婴儿进行艾滋病毒储存疫苗接种并评估其疫苗 3. 研究抗原刺激记忆中的基因特征； T 细胞，包括疫苗接种后的 pTfh，以确定疫苗反应与 HIV 之间的关系拟议的研究可以提供建立新假设、开发生物标志物的见解。 HIV 储存库，用于选择最适合“治愈”相关临床试验的患者，并带来创新根除活跃和潜伏艾滋病毒储存库以实现艾滋病毒持久缓解的治疗策略。