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，结合围产期感染婴儿及时开始联合抗逆转录病毒治疗（cART），是否能够充分改变前病毒库的大小和分布，以促进病毒缓解，在那里，cART可以在没有病毒反弹的情况下停止。HIV-1缓解的一个主要障碍是早期建立潜伏的细胞储存库，允许具有复制能力的病毒终生存在。在婴儿中迅速启动cART的机会可能严重限制或中止这些长期存在的HIV-1储存库的形成。这一概念在最近的密西西比儿童案例中得到了例证，该儿童在31小时大时开始cART，导致HIV-1缓解。我们特别假设，在HIV-1感染主要是胎儿免疫系统的背景下，早期或非常早期的cART限制了HIV-1储存库在长寿命的中央记忆CD4+ T细胞中的大小、分布和复制能力，最终允许HIV-1缓解。在三个不同的队列围产期感染儿童跨越新生儿期

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.