IMPACT OF HIV-1 GENOTYPE ON THERAPY RESPONSE IN CHILDREN

描述：病毒载量和CD 4 T淋巴细胞水平，通常应用 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，特别是那些出现不一致治疗反应的患者。 初始治疗的选择至关重要，因为不能抑制病毒 复制可导致对替代治疗的交叉抗性。复杂 联合治疗需要更多样化的生物标志物库， 对指导HIV感染最佳治疗设计的预后意义 对蛋白酶抑制剂初治的患者。建议的目标 临床研究的目的是确定具有预后价值的新生物标志物， 用于区分启动后的病毒和免疫结果 抗逆转录病毒疗法初步研究表明， 蛋白酶基因型与治疗结果之间的关系。拟议 研究将解决两个假设： 蛋白酶提供病毒和免疫结果的预后标志物， 免疫抑制患者的联合治疗， 除了蛋白酶和/或宿主因子之外， 显示CD 4 T细胞减少的患者的治疗结果的预后指标 尽管病毒水平有所回升，但仍进行了重建。为了检验这些假设， 制定了四个具体目标，以评估：之间的关系 HIV-1蛋白酶中天然存在的氨基酸多态性，反向 转录酶和gag，以及对联合抗逆转录病毒疗法的应答; 2. 24周治疗期间病毒基因型变化的预后意义 和表型，如通过共受体使用和复制的变化所测量的， 巨噬细胞，结果显示免疫重建和高 响应于治疗的病毒负荷; 3.能力之间的关系 免疫重建，如通过TCR库的分子分析所测量的， CD 45 RA和CD 45 RO亚群，以及治疗结果;以及4. 24小时后的变化， 治疗48周后，病毒基因型、表型和免疫反应程度 重建作为疾病进展的中间标志物。研究 研究设计是一项对120名HIV感染儿童的纵向队列研究， 青少年，未经蛋白酶抑制剂治疗，病毒水平高，和 抑制CD 4 T细胞计数。多变量方法将识别新的 生物标志物，导致设计改进的，个性化定制的协议， 对感染HIV- 1的病人开始治疗。

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.