Systems Biology of Immune Reconstitution in HIV / AIDS

描述(申请人提供)：艾滋病毒研究中的一个主要挑战是恢复艾滋病毒感染者的免疫功能。HIV感染会导致CD4T细胞耗尽，导致免疫缺陷和死亡。HAART诱导大多数获得持久病毒学抑制的人的CD4T细胞计数恢复到正常水平。然而，CD4T细胞恢复的大小是可变的，在HAART上实现病毒学抑制的很大一部分人的CD4T细胞恢复较差。药物滥用人口面临的独特挑战包括，在积极滥用药物或其人口特征对获得保健服务产生不利影响的个人中，难以实现持续遵守HAART。此外，药物滥用和丙型肝炎病毒合并感染可能会影响对HAART的反应。这项建议的总体目标是了解导致艾滋病毒感染者免疫功能恢复的机制，这些人在HAART启动后实现了持久的病毒学抑制。工作假说是，在HAART启动后获得持久的病毒学抑制和良好的CD4T细胞恢复的个体，在CD4T细胞恢复较差的个体中，CD4T细胞的表观遗传修饰具有协调的改变模式，并导致CD4T细胞功能障碍。我们将使用系统生物学方法来识别早期表观遗传学特征，这些特征预测在HAART成功启动后，从Mac和活着的队列中恢复HIV感染者的CD4T细胞。表观遗传学图谱数据将与临床数据、基因表达图谱和机制研究相结合，以更好地理解早期表观遗传学特征、疾病标记和潜在机制之间的关系。这些研究将有助于更好地理解静脉注射吸毒者和其他感染艾滋病毒的高危人群中决定CD4T细胞恢复的机制，并可能确定新的治疗策略

DESCRIPTION (provided by applicant): 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 strategi