Functional Genomic Analysis of HIV-1 Infection in LTs

描述（由申请人提供）：淋巴组织是HIV-1在抗逆转录病毒治疗前复制、持续和病理的主要部位。治疗抑制病毒复制后，病理改变可在不同程度上逆转。为了确定HIV-1感染淋巴组织病理和修复过程的分子基础，我们对HIV-1感染患者治疗前后淋巴结活检组织的基因表达进行了初步的微阵列研究。该研究揭示了一组与宿主防御、炎症病理和组织修复相关的治疗应答基因。拟议研究的总体目标是扩展基因谱研究，以进一步了解淋巴组织中HIV-1感染的发病机制和对治疗的反应，从而转化为最佳治疗时机和有效性。为此，在特定目标1中，将有更多处于HIV-1感染不同阶段的患者在抗逆转录病毒治疗前后接受淋巴结活检以进行微阵列分析。在具体目标2中，将使用原位杂交、免疫组织化学染色和定量图像分析来将基因表达的变化与细胞、解剖部位和结构联系起来。总的来说，对病理和修复过程的见解可能导致减少感染病理后果的新方法和增强免疫重建的新治疗策略。

DESCRIPTION (provided by applicant): Lymphatic tissues are the major site of HIV-1 replication, persistence and pathology prior to anti-retroviral treatment. After treatment suppresses viral replication, the pathological changes can be reversed to a variable extent. With the objective of identifying molecular bases for the pathological and reparative processes in HIV-1 infected lymphatic tissues, a preliminary microarray study was undertaken of gene expression in lymph node biopsies from HIV-1 infected patients before and after treatment. The study revealed a set of treatment-responsive genes related to host defenses, inflammatory pathology, and tissue repair. The overall objective of the proposed studies is to extend the gene profiling studies to gain further insight into the pathogenesis of HIV-1 infection in lymphatic tissues and the response to treatment that will translate into optimal timing and effectiveness of treatment. To this end, in specific aim 1 larger numbers of patients at different stages of HIV-1 infection will undergo lymph node biopsies for microarray analysis prior to and after antiretroviral treatment. In specific aim 2, in situ hybridization, immunohistochemical staining and quantitative image analysis will be used to link changes in gene expression to cells and anatomic sites and structures. Collectively, insights into pathological and reparative processes could lead to new approaches to decreasing the pathological consequences of infection and to new therapeutic strategies to enhance immune reconstitution.