Systems Biology of Immune Reconstitution in HIV / AIDS

描述（由申请人提供）：HIV研究的一个主要挑战是恢复HIV感染者的免疫功能。HIV感染导致CD4 T细胞耗竭，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个体恢复CD4 T细胞计数到正常水平。然而，CD4 T细胞恢复的幅度是可变的，并且在HAART上实现病毒学抑制的个体中有很大一部分CD4 T细胞恢复较差。药物滥用人群面临的独特挑战包括，积极滥用药物或具有不利影响获得保健服务的人口特征的个人难以始终坚持HAART治疗。此外，药物滥用和丙型肝炎病毒合并感染可能影响对HAART的反应。该建议的总体目标是了解在HAART启动后获得持久病毒学抑制的hiv感染者中导致免疫功能恢复的机制。工作假设是，在HAART启动后获得持久病毒学抑制和良好CD4 T细胞恢复的个体在CD4 T细胞中具有协调的表观遗传修饰模式，这种模式被改变并导致CD4 T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特征，预测来自MACS和ALIVE队列的hiv感染者在开始成功的HAART后CD4 T细胞的恢复。表观遗传作图数据将与临床数据、基因表达谱和机制研究相结合，以更好地理解早期表观遗传特征、疾病标志物和潜在机制之间的关系。这些研究将有助于更好地了解静脉吸毒者和其他感染艾滋病毒的高危人群中决定CD4 T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