Early Antiretroviral Therapy and HIV Remission in Perinatal Infection

围产期感染的早期抗逆转录病毒治疗和艾滋病毒缓解

• 批准号: 9258459
• 负责人: Yvonne J. Bryson
• 金额: $ 116.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258459
• 关键词: Acquired Immunodeficiency Syndrome; Adolescent; Age; Area; Attenuated; Biological Assay; Birth; CD4 Positive T Lymphocytes; Cells; Characteristics; Child; Childhood; Clinical Trials; Competence; Complementary DNA; Development; Disease remission; Event; FOXP3 gene; Generations; Genome; Goals; HIV; HIV-1; Highly Active Antiretroviral Therapy; Hour; Immune response; Immune system; Immunity; Immunologic Factors; Immunologics; Infant; Infection; Inflammation; International Maternal Pediatric Adolescent AIDS Clinical Trials; Knowledge; Long Terminal Repeats; Mission; Mississippi; Molecular Immunology; Mutation; Myelogenous; Myeloid Cells; Neonatal; Perinatal; Perinatal Infection; Persons; Phenotype; Regulatory T-Lymphocyte; Reporting; Research; Research Priority; Reverse Transcription; T-Lymphocyte; Testing; United States National Institutes of Health; Vial device; Viral; Viral reservoir; Virus; Virus Replication; Work; antiretroviral therapy; cohort; fetal; follow-up; immune activation; improved; infancy; insight; memory CD4 T lymphocyte; neonatal immune system; neonate; optimism; public health relevance; response; viral rebound; virology; virus culture; young adult

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.

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，加上围产期感染的婴儿中迅速启动抗逆转录病毒疗法（CART）是否可以充分改变te的大小和病毒储量的分布，以促进病毒缓解，可以促进CART不得停止，而无需停止Viremective viremective viremecy rebound。 HIV-1缓解的主要障碍是早期建立潜在的细胞库，该储层允许终生持久地持久复制能力的病毒。迅速在婴儿中启动购物车的机会可能严重限制或流产这些长期寿命的HIV-1水库的形成。在最近的密西西比儿童的案例中，这一概念被举例说明了，该案例在31小时时开始，导致HIV-1缓解。我们特别假设在主要胎儿免疫系统的HIV-1感染中，早期或非常早的手推车限制了HIV-1储层在长期寿命的中央记忆CD4+ T细胞中的大小，分布和复制能力，最终允许HIV-1缓解。在三个不同的围产期感染的儿童中，跨越新生儿期 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近脱释放表明在很早或提早开始启动后戒断的适当时机，3）确定是否是 新生儿CD4+ T细胞的感染与HIV-1整合事件的减少和复制缺陷的基因组有关，这些基因组允许在很早的货车中启动的新生儿中清除HIV-1，并且4）确定出生时胎儿T和/或髓样细胞的占主导地位是否与受约束性病毒库的快速衰减相关。拟议的项目 将提高对早期/非常早期HAART长期病毒学和免疫学影响的科学知识对现在有可能生存到年轻成年的婴儿的科学知识。它还将提供有关导致HIV-1储层形成的早期感染事件的见解，以及迅速抗逆转录病毒疗法是否会导致HIV-1缓解或治愈，从而使HIV-1感染的儿童保留一生的治疗时间。这些研究与美国国立卫生研究院的研究使命有直接相关，在那里找到实现病毒缓解或治愈的方法是最重要的 研究优先领域。