Systems Biology of Immune Reconstitution in HIV / AIDS

摘要 艾滋病毒研究中的一大挑战是恢复艾滋病毒感染者的免疫功能。HIV感染 导致CD4T细胞耗尽，导致免疫缺陷和死亡。HAART诱导CD4T细胞恢复 在实现持久病毒学抑制的大多数人中，病毒计数达到正常水平。然而， CD4T细胞回收率的大小是可变的，是实现病毒学研究的一个重要亚群 抑制HAART后，CD4T细胞恢复较差。吸毒人群面临的独特挑战包括 在积极滥用药物或患有艾滋病的个人中实现持续遵守HAART的难度 对获得保健服务产生不利影响的人口统计特征。此外，药物滥用和丙型肝炎病毒 混合感染可能影响对HAART的反应。这项建议的总体目标是理解 导致获得持久病毒学的艾滋病毒感染者免疫功能恢复的机制 HAART启动后的抑制。工作假说是，达到持久目标的个人 HAART启动后的病毒学抑制和良好的CD4T细胞恢复具有协调模式 CD4T细胞的表观遗传修饰发生改变，并导致以下患者的CD4T细胞功能障碍 CD4T细胞恢复较差。我们将使用系统生物学的方法来识别早期的表观遗传特征 预测从Mac和以下存活队列中HIV感染者的CD4T细胞的恢复 启动成功的HAART。表观遗传图谱数据将与临床数据、基因表达 为了更好地理解早期表观遗传特征之间的关系， 疾病标记物和潜在机制。这些研究将导致对机制的更好理解 决定静脉注射吸毒者和其他感染艾滋病毒和艾滋病的高危人群的CD4T细胞恢复 可能会发现新的治疗策略，以改善这些人群中CD4T细胞的恢复。

Abstract A major challenge in HIV research is to restore immune function in HIV-infected individuals. HIV infection causes CD4 T cell depletion, leading to immunodeficiency and death. HAART induces restoration of CD4 T cell counts to normal levels in a majority of individuals who achieve durable virologic suppression. However, the magnitude of CD4 T cell recovery and is variable and a significant subset of individuals who achieve virologic suppression on HAART have poor CD4 T cell recovery. Unique challenges in drug abusing populations include the difficulty of achieving consistent adherence to HAART in individuals who are actively abusing drugs or have demographic characteristics that adversely influence health care access. Furthermore, drug abuse and HCV co-infection may influence responses to HAART. The overall goal of this proposal is to understand mechanisms that lead to recovery of immune function in HIV-infected individuals who achieve durable virologic suppression following HAART initiation. The working hypothesis is that individuals who achieve durable virologic suppression and good CD4 T cell recovery following HAART initiation have a coordinated pattern of epigenetic modification in CD4 T cells that is altered and leads to CD4 T cell dysfunction in individuals who have poor CD4 T cell recovery. We will use systems biology approaches to identify early epigenetic signatures that predict restoration of CD4 T cells in HIV-infected individuals from the MACS and ALIVE cohorts following initiation of successful HAART. Epigenetic mapping data will be integrated with clinical data, gene expression profiling, and mechanistic studies to better understand relationships between early epigenetic signatures, disease markers, and underlying mechanisms. The studies will lead to a better understanding of mechanisms that determine CD4 T cell restoration in IV drug abusers and other at-risk populations infected with HIV and may identify new therapeutic strategies to improve restoration of CD4 T cells in these populations.