Pediatric Immune Correlates of Early Anti-HIV Therapy

早期抗 HIV 治疗的儿科免疫相关性

• 批准号: 6843339
• 负责人: Luis J Montaner
• 金额: $ 47.03万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6843339
• 关键词: AIDS /HIV test; AIDS therapy; Africa; HIV infections; T lymphocyte; antiAIDS agent; blood cell count; cell population study; clinical research; clinical trials; dendritic cells; disease /therapy duration; human immunodeficiency virus; human subject; human therapy evaluation; immunity; infant human (0-1 year); interferon gamma; interleukin 12; longitudinal human study; pathologic process; pediatric AIDS; pediatric pharmacology; preschool child (1-5); virus load

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to study the effects of early antiretroviral therapy (ART) in HIV-infected infants and the functional reconstitution/maturation of antiviral effector mechanisms of the innate/adaptive immune system to identify correlates of delayed disease progression and possible targets for immuno-therapy. Our short-term goal, specifically addressed by this 5 year proposal covering 4 years of follow-up on 120 children, is to (a) characterize and identify the innate and adaptive immunological outcomes of early 9 or 21 months of therapy in infants infected with HIV at birth and (b) correlate outcomes to clinical progression within a period of 2-3 years of follow-up after stopping therapy. This proposal represents an immunology sub-study to a parent NlH-funded clinical trial of 375 children with perinatal HIV infection in South Africa designed to compare the efficacy, toxicity and tolerability of early ART for 9 or 21 months started in <3 month-old infected infants when compared to an infant cohort left untreated until disease progression (<20 CD4%). The parent trial with an anticipated start date of August 2004 will determine if an early and limited ART intervention before disease progression, potentially applicable to a broader cohort of infants, can reduce onset of early death and extend subsequent time to disease progression once off therapy. Based on the clinical design of the parent study including three treatment arms (9 months of ART: i.e., stop ART at age of 1, 21 months of ART: i.e., stop ART at age of 2, and no ART) with ART initiated (or reinitiated) in all once CD4% drops below 20%, the primary hypothesis for the proposed immunology sub-study is that >9 months of ART initiated by three months of age will have a significant impact on the maturation and development of antiviral effector mechanisms (development and retention of plasmacytoid CD123+ dendritic cell, CD56+ Natural Killer cells and CD4+/CD8+ proliferative antiviral responses) that will be positively associated with a delay of disease progression. We will test our hypothesis in a longitudinal study of 40 children per parent-trial arm (120 total) by quantifying the functional presence and association with disease progression of (a) frequencies of circulating dendritic cell, NK and T cell subsets, (b) proliferative/cytokine responses against consensus HIV-1 clade C Gag in CD4 and CD8 T-cell subsets, and (c) proliferative/cytokine responses against autologous viral sequences. This proposal represents a unique opportunity to characterize immune correlates of early treatment in HIV-infected infants in relation to disease progression by combining a recently NIH-funded pediatric study in South Africa with our >40 months experience studying adaptive/innate immune outcomes in HIV-1 infected children using limited numbers of cells. This study represents an international collaboration between The Wistar Institute, The University of Witswatersrand, the HIV perinatal unit of the Chris Hani-Baragwanath Hospital, Tygerberg Children's Hospital, the South African National Institute for Communicable Diseases, and the University of Pennsylvania.

描述（由申请人提供）：本提案的长期目标是研究早期抗逆转录病毒治疗（ART）对HIV感染婴儿的影响以及先天/适应性免疫系统抗病毒效应机制的功能重建/成熟，以确定延迟疾病进展的相关性和免疫治疗的可能靶点。我们的短期目标是（a）描述和确定出生时感染HIV的婴儿接受治疗的前9个月或21个月的先天性和适应性免疫结果，（B）在停止治疗后2-3年随访期间将结果与临床进展相关联。该提案代表了对南非375名患有围产期HIV感染的儿童的父母NIH资助的临床试验的免疫学子研究，该临床试验设计为比较在<3个月大的感染婴儿中开始的9个月或21个月的早期ART的功效、毒性和耐受性，当与不治疗直到疾病进展（<20CD4%）的婴儿队列相比时。预计开始日期为2004年8月的母试验将确定疾病进展前的早期和有限的ART干预（可能适用于更广泛的婴儿队列）是否可以减少早期死亡的发生，并延长停止治疗后疾病进展的时间。基于母研究的临床设计，包括三个治疗组（9个月的ART：即，在1岁时停止抗逆转录病毒治疗，21个月的抗逆转录病毒治疗：即，2岁时停止抗逆转录病毒治疗，未开始抗逆转录病毒治疗）一旦CD4%下降到20%以下，所有患者（或重新开始），所提出的免疫学子研究的主要假设是，在3个月大时开始>9个月的ART将对抗病毒效应机制的成熟和发展产生显著影响（浆细胞样CD 123+树突状细胞、CD 56+自然杀伤细胞和CD 4 +/CD 8+增殖性抗病毒应答的发展和保留），这将与疾病进展的延迟正相关。我们将在一项纵向研究中检验我们的假设，每个父母试验组有40名儿童（总共120例）通过定量以下的功能存在及其与疾病进展的关联：（a）循环树突细胞、NK和T细胞亚群的频率，（B）CD 4和CD 8 T细胞亚群中针对共有HIV-1进化枝C Gag的增殖/细胞因子应答，和（c）针对自体病毒序列的增殖/细胞因子应答。该提案代表了一个独特的机会，通过将最近NIH资助的南非儿科研究与我们使用有限数量的细胞研究HIV-1感染儿童的适应性/先天性免疫结果的40个月经验相结合，来表征HIV感染婴儿早期治疗与疾病进展相关的免疫相关性。这项研究代表了Wistar研究所，Witswatersrand大学，Chris Hani-Baragwanath医院，Tygerberg儿童医院，南非国家传染病研究所和宾夕法尼亚大学之间的国际合作。