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: 8049900
• 负责人: Luis J Montaner
• 金额: $ 51.5万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-17 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049900
• 关键词: Address; Adult; African; Age; Age-Months; Anti-HIV Therapy; Anti-Retroviral Agents; Antigen-Presenting Cells; Antiviral Agents; Antiviral Response; Autologous; Birth; Blood Circulation; CCR5 gene; CD28 gene; CD8B1 gene; CXCR4 gene; Cell Count; Cell physiology; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Collaborations; Communicable Diseases; Consensus; Data; Dendritic Cells; Development; Disease Progression; Drops; Early treatment; Frequencies; Funding; Gagging; Goals; HIV; HIV Infections; HIV-1; Hospitals; IL3RA gene; Immune; Immune system; Immunology; Infant; Infection; Influenza; Institutes; International; Intervention; Left; Longitudinal Studies; Memory; Mixed Lymphocyte Culture Test; Myelogenous; NCAM1 gene; Natural Killer Cells; Outcome; Parents; Pediatric Hospitals; Pennsylvania; Perinatal; Philadelphia; Resources; SELL gene; South Africa; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Toxic effect; Universities; Viral; antiretroviral therapy; arm; base; clinical material; cohort; comparative efficacy; cytokine; design; early onset; experience; follow-up; reconstitution; response

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）：本申请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因素和免疫治疗的可能靶点。我们的短期目标是(a)对出生时感染艾滋病毒的婴儿进行治疗的早期9个月或21个月的先天和适应性免疫结果进行表征和识别，(b)将结果与停止治疗后2-3年随访期间的临床进展相关联。该提案代表了一项由nlh资助的南非375名围产期HIV感染儿童临床试验的免疫学亚研究，旨在比较<3个月感染婴儿开始的9或21个月早期抗逆转录病毒治疗的疗效、毒性和耐受性，并与未治疗直至疾病进展（< 20cd4%）的婴儿队列进行比较。预计于2004年8月开始的家长试验将确定在疾病进展之前进行早期和有限的抗逆转录病毒治疗干预（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。基于本研究的临床设计，包括三个治疗组(ART治疗9个月：即在1岁时停止ART治疗，ART治疗21个月：即，2岁停止抗逆转录病毒治疗，不进行抗逆转录病毒治疗)，一旦CD4%降至20%以下，全部开始（或重新开始）抗逆转录病毒治疗，该免疫学子研究的主要假设是，3个月大开始的> - 9个月的抗逆转录病毒治疗将对抗病毒效应机制的成熟和发展（浆细胞样CD123+树突状细胞的发育和保留）产生重大影响。CD56+自然杀伤细胞和CD4+/CD8+增殖性抗病毒反应)将与疾病进展的延迟呈正相关。我们将在一项纵向研究中检验我们的假设，每个家长试验组有40名儿童（总共120名），通过量化(a)循环树突状细胞、NK和T细胞亚群的频率，(b) CD4和CD8 T细胞亚群中针对HIV-1进化枝C Gag的增殖/细胞因子反应，以及(C)针对自体病毒序列的增殖/细胞因子反应的功能存在及其与疾病进展的关联。该建议提供了一个独特的机会，通过结合最近美国国立卫生研究院资助的南非儿科研究和我们40个月的经验，利用有限数量的细胞研究HIV-1感染儿童的适应性/先天免疫结果，来表征hiv感染婴儿早期治疗与疾病进展相关的免疫相关因素。这项研究是Wistar研究所、Witswatersrand大学、Chris Hani-Baragwanath医院艾滋病毒围产期部门、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。