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: 7187354
• 负责人: Luis J Montaner
• 金额: $ 59.09万
• 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/7187354
• 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; CD4 Positive T Lymphocytes; 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; Rate; Resources; SELL gene; South Africa; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Toxic effect; Universities; Upper arm; Viral; antiretroviral therapy; base; cohort; 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(申请人提供)：这项建议的长期目标是研究艾滋病毒感染婴儿的早期抗逆转录病毒治疗(ART)的效果，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，以确定延缓疾病进展的相关因素和免疫治疗的可能目标。我们的短期目标是：(A)对出生时感染艾滋病毒的婴儿进行为期9个月或21个月的治疗；(B)在停止治疗后的2-3年内，将治疗结果与临床进展相关联。这项建议代表了一项由NLH资助的针对南非375名患有围产期HIV感染的儿童的临床试验的免疫学子研究，该试验旨在比较从3个月大的感染婴儿开始接受9个月或21个月的早期抗逆转录病毒疗法的疗效、毒性和耐受性，并与直到疾病进展(&lt；20CD4%)才接受治疗的婴儿队列进行比较。预期开始日期为2004年8月的父母试验将确定，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，并在结束治疗后延长随后的疾病进展时间。基于母体研究的临床设计，包括三个治疗组(9个月的ART：即在1岁时停止ART，21个月的ART：即在2岁时停止ART，以及没有ART)，一旦CD4%降至20%以下，全部启动(或重新启动)ART，建议的免疫学次级研究的主要假设是&GT；由3个月龄开始的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产生重大影响(浆细胞样CD123+树突状细胞、CD56+自然杀伤细胞和CD4+/CD8+增殖性抗病毒反应)，这将与疾病进展的延迟正相关。我们将在一项针对40名儿童的纵向研究中验证我们的假设，这项研究是通过量化以下因素的功能存在及其与疾病进展的关系：(A)循环树突状细胞、NK和T细胞亚群的频率；(B)针对CD4和CD8T细胞亚群中一致的HIV-1 C亚群的增殖/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。这项提议代表着一个独特的机会，通过将NIH最近在南非资助的一项儿科研究与我们40个月来使用有限数量的细胞研究HIV-1感染儿童的适应性/先天免疫结果相结合，来表征感染艾滋病毒的婴儿早期治疗与疾病进展的免疫相关性。这项研究是Wistar研究所、Witswatersrand大学、Chris Hani-Baragwanath医院艾滋病毒围产期单元、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。