Early Antiretroviral Therapy and HIV Remission in Perinatal Infection

描述（由申请人提供）：本申请的总体目标是了解新生儿免疫系统的独特特征，结合在围产期感染婴儿中迅速启动联合抗逆转录病毒治疗（cART），是否足以改变前病毒储库的大小和分布，以促进病毒缓解，其中cART可以停止而不会出现病毒血症反弹。HIV-1缓解的一个主要障碍是早期建立潜伏的细胞储库，允许有复制能力的病毒终身持续存在。在婴儿中及时开始cART的机会可能会严重限制或中止这些长寿HIV-1储库的形成。这一概念在最近的密西西比儿童的案例中得到了例证，该儿童在31小时内开始cART，导致HIV-1缓解。我们特别假设，在HIV-1感染的背景下，早期或非常早期的cART主要是胎儿免疫系统限制了HIV-1储库在长寿命的中央记忆CD 4 + T细胞中的大小，分布和复制能力，最终允许HIV-1缓解。在新生儿期的三个不同围产期感染儿童队列中， 通过青少年，包括在国际孕产妇儿科青少年艾滋病临床试验（IMPAACT）网络赞助的一项计划中的临床试验中，我们将使用超灵敏的分子、免疫学和病毒培养测定来：1）在围产期HIV-1感染中，在长期有效的cART下，确认HIV-1前病毒储库的持续衰减并鉴定其驻留的位置，2）确定HIV-1接近缓解的病毒学和免疫学特征，其指示在非常早期或早期cART开始后停止cART的适当时机，3）确定是否 新生儿CD 4 + T细胞的感染与减少的HIV-1整合事件和复制缺陷基因组相关，所述复制缺陷基因组允许在新生儿中清除HIV-1，从而启动非常早期的cART，和4）确定出生时胎儿T和/或骨髓细胞的优势是否与限制性病毒储库的快速衰减相关并预测其快速衰减。拟建项目 将提高对早期/极早期HAART对婴儿的长期病毒学和免疫学影响的科学知识，这些婴儿现在可能存活到年轻的成年。它还将深入了解导致HIV-1储库形成的早期感染事件，以及及时的抗逆转录病毒治疗是否会导致HIV-1缓解或治愈，从而使HIV- 1感染儿童免于终生治疗。这些研究与美国国立卫生研究院的研究使命有直接关系，该研究院的首要任务是找到缓解或治愈病毒的方法。 优先研究领域。

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.