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 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。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，CD4 T 细胞显着增加。尽管研究人员意识到HAART后免疫功能发生了一些变化，但尚未发表的大型研究描述了HIV感染儿童免疫恢复的动态。接受 HAART 治疗的成人的 CD4 T 细胞平均增加了 250 个/uL，并且一些 T 细胞介导的回忆抗原反应恢复 (1)。功能性记忆 T 细胞的这种恢复可能是由于大多数补充的 T 细胞具有“记忆”表型，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 CD4 T 细胞的增加与成年癌症化疗患者中观察到的情况相似，这些患者在 T 细胞耗尽后恢复了完全记忆细胞 (3)。此外，康纳斯等人。据报道，尽管 CD4 细胞计数大幅增加，但开始 HAART 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途径在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。相比之下，年龄依赖性胸腺生成途径可能是 CD4 T 细胞库正常且可持续多样性再生的催化剂。最近在一项针对 HIV 感染儿童的小型研究中观察到 HAART 治疗期间胸腺增大，表明胸腺在该人群中发挥着积极作用 (5)。了解 HIV 感染儿童 T 细胞恢复的发病机制，以及免疫系统对记忆和新抗原作出反应的能力恢复到何种程度，将影响临床治疗并最终影响这些患者的生存。这些发现将明确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) 严重免疫缺陷的儿童在开始 HAART 后 1-2 年内将产生大量 CD4 T 细胞（特别是幼稚表型的细胞）； 2）T细胞的恢复取决于治疗前3个月病毒载量的显着降低，而不取决于治疗6个月后病毒复制的持续抑制； 3）不会因记忆T细胞的克隆删除而发生免疫反应的自发恢复； 4) 新获得的 CD4 T 细胞可以对遇到的抗原产生反应。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 CD4 T 细胞对记忆抗原、破伤风类毒素自发产生淋巴增殖反应的能力，或在破伤风疫苗加强接种后产生反应的能力，2) 评估以下能力：使用甲型肝炎疫苗接种的主要系列来开发针对 T 细胞依赖性抗原的保护性抗体反应； 3) 衡量最后一次疫苗接种后任何反应的持久性。次要目标是： 1) 测量基线和疫苗接种时的 CD4 T 细胞百分比，并将其与免疫反应的建立联系起来； 2) 研究基线时表型“幼稚”和“记忆”T细胞的建立以及疫苗接种时间与免疫反应建立的相关性； 3) 评估新衍生的 CD4 T 细胞对环境抗原念珠菌产生自发细胞介导的免疫反应的能力； 4) 评估对 T 细胞依赖性抗原甲型肝炎产生淋巴增殖反应的能力； 5）评估HAART后功能性免疫的恢复是早期还是晚期； 6) 测量基线、疫苗接种时间和研究完成时（104 周）的 HIV 血浆拷贝数，并将这些与免疫反应的建立联系起来； 7) 评估对感染艾滋病毒的儿童和青少年使用 FDA 许可的疫苗进行多次免疫的安全性； 8) 评估第 100 周时甲型肝炎疫苗加强接种是否会导致甲型肝炎抗体增加。