Infant immune mechanisms of HIV reservoir size and decay

在早期HIV感染期间，病毒稳定地整合在长期存活的细胞库中， 持续抗逆转录病毒治疗（ART）。在早期急性HIV感染期间开始ART可能会限制病毒库 大小、减少免疫激活、改善治疗结果和治疗后病毒学控制 和儿童关于撒哈拉以南非洲的储层动态和决定因素的数据很少， 是全球儿童艾滋病感染率最高的地区。我们之前已经证明了抗体的影响- 依赖性细胞毒性（ADCC）对婴儿HIV感染和疾病控制的影响。我们还 在婴儿期，自然杀伤（NK）细胞群体表现出明显的可塑性， 抑制艾滋病毒和成人队列中的感染。这些免疫反应可能会影响 水库建设和衰减。了解这些决定因素可以为疫苗或治疗提供信息 加快消除水库的战略。 我们对婴儿和年龄较大的儿童进行了>5-10年的连续PBMC和血浆收集， 在生命第一年开始抗逆转录病毒治疗的儿童亚组中， 这些群体的压制。我们建议利用这些独特的机制病毒学/免疫学研究 储存库，并延长这些儿童的随访，以跟踪更长期的水库变化（自 一些儿童开始接受抗逆转录病毒治疗）。我们的首要目标是确定油藏动态和衰减使用 数学建模和识别油藏递减和规模的免疫决定因素。该项目将由 由多个PI（MPI）：约翰-斯图尔特博士和雷曼。结合我们在儿科艾滋病方面的专业知识 分子流行病学（约翰-斯图尔特，沃斯塔瓦）病毒学（雷曼，奥弗博），免疫学（斯莱克，布利什） 和建模（Holte，Matsen），我们建议对纵向油藏动态进行建模，并确定 婴儿感染艾滋病毒的时机、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。这些研究将提供新的 撒哈拉以南非洲婴儿期和幼儿期的储层动力学数据， 免疫激活、ADCC和自然杀伤细胞表型在水库控制中的潜在影响，以及 最终为改善艾滋病毒长期管理和宿主控制的干预战略提供信息 被感染的孩子

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.