Early Antiretroviral Therapy and HIV Remission in Perinatal Infection

描述(申请人提供)：本申请的总体目标是了解新生儿免疫系统的独特特征，结合围产期感染婴儿迅速开始联合抗逆转录病毒治疗(CART)，是否可以充分改变病毒前体库的大小和分布，以促进病毒缓解，其中CART可以被阻止而不会出现病毒反弹。HIV-1病毒缓解的一个主要障碍是早期建立了潜伏的细胞库，允许复制能力强的病毒终生持续存在。在婴儿中迅速启动CART的机会可能会严重限制或中止这些长期存在的HIV-1宿主的形成。这一概念在最近密西西比州儿童的案例中得到了例证，在该儿童中，31小时开始的CART导致艾滋病毒-1病毒的缓解。我们特别假设，在HIV-1感染以胎儿为主的免疫系统的背景下，早期或非常早期的CART限制了HIV-1储存库的大小、分布和复制能力，最终允许HIV-1缓解。在三个不同的围产期感染儿童队列中 通过青少年，包括在由国际母婴青少年艾滋病临床试验网络(IMPAACT)赞助的计划中的临床试验中，我们将使用超灵敏的分子、免疫学和病毒培养分析来：1)确认围产期HIV-1感染的长期有效CART下HIV-1前病毒储存库的持续腐烂并确定其所在位置；2)确定HIV-1接近缓解的病毒学和免疫学特征，表明在非常早期或早期CART启动后停止CART的适当时机；3)确定是否 新生儿CD4+T细胞感染与HIV-1整合事件减少和复制缺陷基因组有关，这些基因组允许在很早就开始CART的新生儿中清除HIV-1；4)决定出生时胎儿T细胞和/或髓系细胞的优势是否与限制性病毒库的快速衰退有关并预测其迅速衰退。拟议中的项目 将提高关于早期/非常早期HAART对现在有可能存活到成年的婴儿的长期病毒学和免疫学影响的科学知识。它还将提供对导致艾滋病毒-1储存库形成的早期感染事件的洞察，以及及时抗逆转录病毒治疗是否会导致艾滋病毒-1缓解或治愈，从而使感染艾滋病毒-1的儿童不必终生接受治疗。这些研究与美国国立卫生研究院的研究任务直接相关，在那里，寻找实现病毒缓解或治愈的方法是首要任务 研究优先领域。

DESCRIPTION (provided by applicant): The overall goal of this application is to understand whether distinctive features of the neonatal immune system, combined with prompt initiation of combination antiretroviral therapy (cART) in perinatally-infected infants, can sufficiently alter te size and distribution of proviral reservoirs to facilitate viral remission, where cART can be stopped without viremic rebound. A major barrier to HIV-1 remission is the early establishment of latent cellular reservoirs that permit lifelong persistence of replication-competent virus. The opportunity to start cART promptly in infants may severely restrict or abort the formation of these long-lived HIV-1 reservoirs. This concept is exemplified in the recent case of the Mississippi Child in whom cART started by 31 hours of age led to HIV-1 remission. We specifically hypothesize that early or very early cART in the context of HIV-1 infection of a predominantly fetal immune system restricts the size, distribution, and replication-competence of the HIV-1 reservoirs in long-lived central memory CD4+ T cells, eventually permitting HIV-1 remission. In three different cohorts of perinatally-infected children spanning the neonatal period through adolescents, including in a planned clinical trial sponsored by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, we will use ultrasensitive molecular, immunology and virus culture assays to: 1) Confirm ongoing decay of and identify where HIV-1 proviral reservoirs reside under long-term effective cART in perinatal HIV-1 infection, 2) identify a virologic and immunologic profile of HIV-1 near-remission that indicates the appropriate timing of cART cessation after very early or early cART initiation, 3) determine if infection of neonatal CD4+ T cells is associated with diminished HIV-1 integration events and replication-deficient genomes that permit clearance of HIV-1 in neonates initiating very early cART and 4) determine whether a predominance of fetal T and/or myeloid cells at birth is associated with and predictive of rapid decay of a restricted viral reservoir. The proposed project will improve scientific knowledge on the long-term virologic and immunologic effects of early/very early HAART for infants who are now likely to survive to young adulthood. It will also provide insights into the early infection events leading up to HIV-1 reservoir formation and whether prompt antiretroviral therapy will lead to HIV-1 remission or cure, thus sparing HIV- 1 infected children a lifetime of therapy. The studies have direct relevance to the research mission of the National Institutes of Health where finding ways to achieve viral remission or cure is a top research priority area.