Infant immune mechanisms of HIV reservoir size and decay

HIV储存库大小和衰减的婴儿免疫机制

• 批准号: 10200873
• 负责人: Grace John-Stewart
• 金额: $ 66.92万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200873
• 关键词: Acute; Address; Adult; Africa South of the Sahara; Aftercare; Age; Age-Months; Antibodies; Biological Specimen Banks; Breast Feeding; Cell Count; Cells; Child; Collection; Containment; Cryopreservation; Cytomegalovirus; DNA; Data; Disease; Early treatment; HIV; HIV Infections; HIV diagnosis; Half-Life; Immune; Immune response; Immunologic Factors; Immunology; Incidence; Indolent; Infant; Infant Development; Infection; Intervention; Life; Link; Mississippi; Modeling; Molecular Epidemiology; Natural Killer Cells; Pathogenesis; Perinatal; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Play; Population; Population Characteristics; Postpartum Period; Predisposition; RNA; Research; Research Design; Resources; Role; Route; Therapeutic; Time; Treatment outcome; Vaccines; Viral; Viral Pathogenesis; Viral reservoir; Virus; age related; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; co-infection; cohort; cytotoxic; disorder control; early childhood; follow-up; immune activation; improved; infancy; infant infection; latent HIV reservoir; mathematical model; mortality; nonlinear regression; novel; pediatric human immunodeficiency virus; pediatric human immunodeficiency virus infection; postnatal; repository; response; transmission process; viral DNA; virology

During early HIV infection, the virus stably integrates in long-lived cellular reservoirs which persist despite continuous antiretroviral therapy (ART). ART initiation during early acute HIV infection may limit viral reservoir size, reduce immune activation and improve treatment outcomes and post-treatment virologic control in adults and children. There are scant data on reservoir dynamics and determinants from sub Saharan Africa, the region of the world with most global pediatric HIV. We have previously demonstrated influence of antibody- dependent cellular cytotoxicity (ADCC) on infant HIV acquisition and disease control. We have also demonstrated marked plasticity of the natural killer (NK) cell population over the course of infancy and NK suppression of HIV and acquisition in adult cohorts. It is plausible that these immune responses may influence reservoir establishment and decay. Understanding these determinants could inform vaccine or therapeutic strategies to accelerate reservoir eradication. We have followed infants and older children for >5-10 years with serial PBMC and plasma collection and have quantified HIV reservoir in a subset of children who started ART during the first year of life with viral suppression from these cohorts. We propose mechanistic virology/immunogy studies leveraging these unique repositories and to extend follow-up of these children to track longer term reservoir changes (>15 years since ART initiation in some children). Our overarching aim is to determine reservoir dynamics and decay using mathematical modeling and identify immune determinants of reservoir decline and size. This project will be led by multiple PIs (MPIs): Drs. John-Stewart and Lehman. With our combined expertise in pediatric HIV molecular epidemiology (John-Stewart, Wamalwa) virology (Lehman, Overbaugh), immunology (Slyker, Blish) and modeling (Holte, Matsen) we propose to model longitudinal reservoir dynamics, and determine effects of infant timing of HIV acquisition, ART timing, and the influence of infant immune activation, ADCC, and NK population characteristics on reservoir decline and size. These studies will provide novel data on reservoir dynamics during infancy and early childhood from sub Saharan Africa and will elucidate potential influence of immune activation, ADCC, and natural killer phenotype in reservoir containment, and ultimately inform intervention strategies for improved long-term management and reservoir control in HIV infected children.

在早期艾滋病毒感染期间，病毒稳定地整合到长寿命的细胞储存库中，尽管存在 持续抗逆转录病毒治疗（ART）。早期急性艾滋病毒感染期间开始抗逆转录病毒疗法可能会限制病毒储存 大小，减少免疫激活并改善成人的治疗结果和治疗后病毒学控制 和孩子们。关于撒哈拉以南非洲地区的储层动态和决定因素的数据很少， 世界上儿童艾滋病毒感染最多的地区。我们之前已经证明了抗体的影响- 依赖细胞毒性（ADCC）对婴儿艾滋病毒感染和疾病控制的影响。我们还有 证明自然杀伤 (NK) 细胞群在婴儿期和 NK 过程中具有显着的可塑性 抑制艾滋病毒和成人群体中的感染。这些免疫反应可能会影响 水库的建立和衰退。了解这些决定因素可以为疫苗或治疗提供信息 加速消除水库的战略。 我们通过连续 PBMC 和血浆采集对婴儿和年龄较大的儿童进行了超过 5-10 年的跟踪，并已 对在生命第一年开始接受抗逆转录病毒治疗的儿童子集中的艾滋病毒储存库进行了量化 来自这些群体的压制。我们建议利用这些独特的机制进行病毒学/免疫学研究 储存库并延长对这些儿童的随访，以跟踪长期储存库变化（自15年以来） 一些儿童开始接受 ART）。我们的首要目标是利用 数学建模并确定水库衰退和规模的免疫决定因素。该项目将由 由多个 PI (MPI) 负责：Drs.约翰-斯图尔特和雷曼。凭借我们在儿科艾滋病毒方面的综合专业知识 分子流行病学 (John-Stewart, Wamalwa) 病毒学 (Lehman, Overbaugh)，免疫学 (Slyker, Blish) 和建模（Holte，Matsen），我们建议对纵向油藏动态进行建模，并确定 婴儿感染 HIV 时机、ART 时机的影响以及婴儿免疫激活的影响， ADCC 和 NK 种群特征对水库衰退和规模的影响。这些研究将提供新颖的 关于撒哈拉以南非洲婴儿期和幼儿期水库动态的数据，并将阐明 免疫激活、ADCC 和自然杀伤表型对水库遏制的潜在影响，以及 最终为改善艾滋病毒长期管理和储存库控制的干预策略提供信息 受感染的儿童。