PACTG P1006 THE EFFECTS OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) ON TH

PACTG P1006 高活性抗逆转录病毒治疗 (HAART) 对 TH 的影响

• 批准号: 7374980
• 负责人: William Thomas Shearer
• 金额: $ 0.1万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7374980
• 关键词: PACTG; P1006; EFFECTS; HIGHLY; ACTIVE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. HIV-1 infected children treated with multiple potent antiretrovirals have experienced a significant increase in CD4 T cells after the initiation of highly active antiretroviral therapy (HAART). Although researchers are aware there are several changes in the immune function following HAART, no large published studies have delineated the dynamics of immune recovery in HIV-infected children. Adults treated with HAART have had mean increases of 250 CD4 T cells/uL and the return of some T-cell mediated responses to recall antigens (1). This return of functional memory T cells may be due to the fact that the majority of the replenished T cells are of the "memory" phenotype, perhaps elicited by proliferation of peripherally distributed T cells, and presumably independent of recent thymic education (2). This increase in memory CD4 T cells is similar to that seen in adult cancer chemotherapy patients who have a recovery of exclusively memory cells after T cell depletion (3). In addition, Connors et al. reported that the phenotype of T cell regenerated after the initiation of HAART depends on the types of T cells present before therapy despite robust increases in CD4 cell counts (4). The role of the independent thymic pathway in the regeneration of the immune system to a near normal level post- HAART seen in adults may not coincide with the process occurring in children. In contrast, the age dependent thymopoietic pathway may be the catalyst for the regeneration of a normal and sustainable diversity of CD4 T cell repertoire. Thymic enlargement during HAART treatment was recently observed in a small study of HIV-infected children suggesting an active role of the thymus in this population (5). Understanding the pathogenesis of T cell recovery in HIV-infected children and to what extent there is restoration in the ability of the immune system to respond to recall and neo-antigens will impact on the clinical management and ultimately on the survival of these patients. These findings will define the role of vaccines and chemoprophylaxis in disease prevention in these patients. These preliminary data support the assumptions that 1) children with severe immunodepletion will develop significant numbers of CD4 T cells (particularly those of a naive phenotype) for 1-2 years after initiating HAART; 2) the recovery of T cells is dependent on a significant decrease in viral load in the first 3 months of therapy but not on the sustained inhibition of viral replication after 6 months of therapy; 3) the spontaneous recovery of immunologic responses will not occur due to the clonal deletion of memory T cells; and 4) newly acquired CD4 T cells can develop responses to antigens encountered. A multi-center study powered to examine the phenotype and function of T cells regenerated post-HAART initiation is needed to further assess several assumptions supported by the preliminary data. The objectives of this study are:1) To assess the ability of newly derived CD4 T cells to spontaneously develop lymphoproliferative responses to a recall antigen, tetanus toxoid, or to develop responses after booster vaccinations with tetanus vaccine, 2) To assess the ability to develop protective antibody responses to a T cell dependent antigen using a primary series of hepatitis A vaccinations; 3) To measure the durability of any response beyond the last vaccination. Secondary objectives are: 1) To measure CD4 T cell percentage at baseline and at the time of vaccination(s) and to correlate these with the establishment of immune responses; 2) To study the correlation of the establishment of phenotypic "naive" and "memory" T cells at baseline and the time of vaccination(s) with the establishment of immune responses; 3)To assess the ability of newly-derived CD4 T cells to develop spontaneous cell-mediated immune responses to an environmental antigen, candida; 4) To assess the ability to develop lymphoproliferative responses to T cell-dependent antigen, hepatitis A; 5)To assess whether the recovery of functional immunity is seen early or late after HAART; 6)To measure the HIV plasma copy number at baseline, the time of vaccination(s), and at the study completion (104 weeks) and to correlate these with the establishment of immune responses; 7)To assess the safety of giving multiple immunizations with FDA licensed vaccines to HIV-infected children and young adults; and 8)To assess whether a hepatitis A vaccination booster at week 100 will result in an increase in hepatitis A antibody.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。接受多种强效抗逆转录病毒药物治疗的HIV-1感染儿童在开始高效抗逆转录病毒治疗（HAART）后，CD 4 T细胞显著增加。尽管研究人员意识到HAART后免疫功能发生了一些变化，但没有大型发表的研究描述了HIV感染儿童免疫恢复的动态。接受HAART治疗的成人平均增加了250个CD 4 T细胞/uL，并恢复了一些T细胞介导的对回忆抗原的应答（1）。功能性记忆T细胞的恢复可能是由于大多数补充的T细胞具有“记忆”表型，这可能是由外周分布的T细胞增殖引起的，并且可能与最近的胸腺教育无关（2）。这种记忆性CD 4 T细胞的增加与成年癌症化疗患者中观察到的相似，这些患者在T细胞耗竭后恢复了专门的记忆细胞（3）。此外，Connors等人报道，尽管CD 4细胞计数显著增加，但HAART开始后再生的T细胞表型取决于治疗前存在的T细胞类型（4）。在成人中观察到的独立胸腺通路在HAART后免疫系统再生至接近正常水平中的作用可能与儿童中发生的过程不一致。相反，年龄依赖性胸腺生成途径可能是正常和可持续多样性的CD 4 T细胞库再生的催化剂。最近在一项HIV感染儿童的小型研究中观察到HAART治疗期间胸腺增大，表明胸腺在这一人群中发挥积极作用（5）。了解HIV感染儿童T细胞恢复的发病机制以及免疫系统对回忆和新抗原的反应能力恢复到何种程度将影响临床管理并最终影响这些患者的生存。这些发现将确定疫苗和化学预防在这些患者疾病预防中的作用。这些初步数据支持以下假设：1）严重免疫耗竭的儿童将产生大量的CD 4 T细胞2）T细胞的恢复依赖于治疗前3个月内病毒载量的显著降低，但不依赖于治疗6个月后病毒复制的持续抑制; 3）由于记忆T细胞的克隆缺失，免疫应答的自发恢复不会发生;以及4）新获得的CD 4 T细胞可以对遇到的抗原产生应答。需要一项多中心研究来检查HAART启动后再生的T细胞的表型和功能，以进一步评估初步数据支持的几个假设。本研究的目的是：1）评估新衍生的CD 4 T细胞自发产生对回忆抗原（破伤风类毒素）的淋巴增殖性应答的能力，或在破伤风疫苗加强接种后产生应答的能力，2）评估使用甲型肝炎疫苗初次系列接种产生对T细胞依赖性抗原的保护性抗体应答的能力; 3）测量最后一次疫苗接种后任何应答的持久性。次要目的是：1）测量基线和疫苗接种时的CD 4 T细胞百分比，并将其与免疫应答的建立相关联; 2）研究基线和疫苗接种时表型“初始”和“记忆”T细胞的建立与免疫应答的建立的相关性; 3）评估新衍生的CD 4 T细胞对环境抗原念珠菌产生自发细胞介导的免疫应答的能力; 4）评估对T细胞依赖性抗原甲型肝炎产生淋巴增殖应答的能力; 5）评估HAART后早期或晚期是否观察到功能性免疫的恢复; 6）测量基线、疫苗接种时和研究完成时的HIV血浆拷贝数（104周），并将其与免疫反应的建立相关联; 7）评估对感染艾滋病毒的儿童和年轻人使用FDA许可的疫苗进行多次免疫接种的安全性;及8）评估在第100周加强接种甲型肝炎疫苗会否导致甲型肝炎抗体增加。