IMPACT OF HIV-1 GENOTYPE ON THERAPY RESPONSE IN CHILDREN

说明：病毒载量和CD4T淋巴细胞水平，一般应用 联合抗逆转录病毒治疗的预后指标是 没有足够的措施来预测许多艾滋病毒感染者的病毒和免疫反应 患者，尤其是那些产生不和谐治疗反应的患者。 选择初始治疗至关重要，因为未能抑制病毒 复制可导致对替代治疗的交叉耐药。复合体 联合治疗需要更多样化的生物标记物 指导HIV感染最佳治疗方案设计的预后意义 在那些对蛋白酶抑制剂天真的患者中。建议的目标是 临床研究是确定具有预后价值的新生物标记物 用于区分启动后的病毒和免疫结果 抗逆转录病毒治疗。初步研究表明， 蛋白水解酶基因分型与治疗结果的关系建议数 研究将解决两个假设：自然遗传多态在 蛋白水解酶为病毒和免疫结果提供预后标志 免疫抑制患者的联合治疗，以及病毒基因 除了蛋白酶和/或宿主因素之外的决定因素提供了新的 CD4T细胞阳性患者治疗结果的预后指标 尽管病毒水平有所回升，但仍在进行重建。为了检验这些假设， 设计了四个具体的目标来评估：1. HIV-1蛋白酶中自然产生的氨基酸多态性，反向 转录酶、GAG和联合抗逆转录病毒治疗的反应； 24周治疗期间病毒基因型变化对预后的意义 和表型，通过共同受体的使用和复制的变化来衡量 巨噬细胞，对表现为免疫重建和高水平的患者的预后 治疗反应中的病毒负担；3.治疗能力与 通过TCR谱系的分子分析来衡量免疫重建 CD45RA和CD45RO亚群及治疗结果； 48周的病毒基因型、表型和免疫程度的治疗 重建作为疾病进展的中间标志。这项研究 设计是一项纵向队列研究，对120名感染艾滋病毒的儿童和 未经蛋白酶抑制剂治疗的青少年，病毒水平高，以及 抑制了CD4T细胞计数。多变量方法将识别出新的 生物标志物，导致设计改进的、单独定制的方案以 开始对感染艾滋病毒-1的患者进行治疗。

DESCRIPTION: Viral load and CD4 T lymphocyte levels, generally applied prognostic measures of outcome to combination antiretroviral therapy, are insufficient measures to predict viral and immune response by many HIV-infected patients, particularly those who develop a discordant treatment responses. Selection of initial therapy is critical, as failure to suppress viral replication can lead to cross-resistance to alternative treatments. Complex combination therapies necessitate a more diverse repertoire of biomarkers with prognostic significance to guide design of optimal treatments for HIV infection among patients who are naive to protease inhibitors. The goal of the proposed clinical research is to identify novel biomarkers that have prognostic value for distinguishing viral and immune outcomes following initiation of antiretroviral therapy. Preliminary studies demonstrate a significant relationship between protease genotype and treatment outcome. The proposed research will address two hypotheses: that natural genetic polymorphisms in protease provide prognostic markers for viral and immune outcomes to combination therapy in immune suppressed patients, and that viral genetic determinants in addition to protease and/or host factors provide novel prognostic measures of treatment outcome for patients who show CD4 T cell reconstitution despite a resurgence in virus levels. To test these hypotheses, four specific aims have been designed to evaluate: l. a relationship between naturally occurring amino acid polymorphisms in HIV-1 protease, reverse transcriptase, and gag, and response to combination antiretroviral therapy; 2. prognostic significance of changes during 24 weeks of therapy in viral genotype and phenotype, as measured by changes in co-receptor usage and replication in macrophages, to outcome in patients who display immune reconstitution and high viral burden in response to therapy; 3. relationship between capacity for immune reconstitution, as measured by molecular analyses of TCR repertoire in CD45RA and CD45RO subsets, and treatment outcome; and 4. changes after 24 and 48 weeks of therapy in viral genotype, phenotype, and extent of immune reconstitution as intermediate markers for disease progression. The research design is a longitudinal, cohort study of 120 HIV-infected children and adolescents, untreated with protease inhibitors, with high viral levels, and suppressed CD4 T cell counts. The multivariate approach will identify novel biomarkers that lead to design of improved, individually tailored protocols to initiate therapy for patients infected by HIV- 1.