HIV AND HCV DISEASE PROGRESSION IN WOMEN ON HAART

描述（由申请人提供）：HIV感染引起全身免疫激活，涉及免疫系统的先天性和适应性臂，增加AIDS和HIV相关非AIDS病症（HANA），即使采用成功的HAART治疗。我们的研究表明，高水平的免疫激活和衰老在HIV疾病的早期被观察到，并且与艾滋病、心血管疾病和肝脏疾病相关，特别是在HCV合并感染的女性中。此次更新的总体目标是继续检查这种免疫超活化状态的机制和后果及其对加速疾病的影响。我们将评估异常细胞因子产生的后果，这些细胞因子可能促进纤维化或组织损伤，并改变T细胞成熟、调节和免疫功能。我们发现，合并感染的肝纤维化妇女的调节性T细胞显著减少，衰老和终末分化及效应记忆T细胞的百分比增加，表明免疫失调可能加速“炎症”和终末器官疾病。在这项提案中，我们将全面研究长期激活和免疫失调对WIHS妇女的临床结果的影响。使用多参数流式细胞术、真实的时间PCR和PCR阵列技术，我们开发了系统地评估影响疾病的免疫学和病毒学因素的平台。我们进行了复杂的验证实验，允许同时评估可溶性和细胞生物标志物，免疫激活，耗竭，衰老和调节的分子基因特征，以及来自一个样品的病毒学研究。我们的中心假设是，HIV相关的免疫失调和HCV感染伴肝功能障碍维持这种免疫超活化状态，导致免疫衰竭和衰老以及HANA病症的更快进展，即使使用有效的HAART。此外，肝病将在决定免疫学，病毒学和临床结果方面发挥重要作用，特别是随着女性年龄的增长和进入更年期。我们的具体目标是：具体目标1）确定HAART成功治疗的单一和合并感染女性中长期免疫激活的决定因素和后果，具体目标2）评估促进免疫激活、衰老、衰竭和临床结局进展的分子机制中涉及的基因表达模式。对于特定目标1，我们将纵向比较细胞因子以及活化和免疫调节的可溶性和细胞标志物的水平，并确定对免疫衰老/衰竭和疾病结局的影响。对于特异性目标2，我们将使用真实的时间PCR阵列技术评估免疫的内在宿主基因签名途径，并将评估与免疫活化、耗竭和衰老相关的干扰素应答。这些研究将确定长期激活和失调对衰老和衰竭的影响，以及HCV合并感染的作用，以期制定可能预防持续过度激活和发病的治疗策略。

DESCRIPTION (provided by applicant): HIV infection causes generalized global immune activation involving both the innate and adaptive arms of the immune system increasing AIDS and HIV-related non-AIDS conditions (HANA), even with successful HAART treatment. Our studies demonstrate that high levels of immune activation and senescence are seen early in HIV disease and are associated with incident AIDS, cardiovascular and liver disease especially in HCV co- infected women. The overall goal of this renewal is to continue examining mechanisms and consequences of this immune hyperactivation state and its impact on accelerated disease. We will evaluate the consequences of aberrant cytokine production that may promote fibrogenesis or tissue damage and alter T cell maturation, regulation and immune function. We find that co-infected women with liver fibrosis have significantly fewer regulatory T cells and increased percentage of senescent and terminally differentiated and effector memory T cells, indicating that immune dysregulation may accelerate "inflammaging" and end organ disease. In this proposal, we will comprehensively investigate the effect of long-term activation and immune dysregulation on clinical outcome in a well characterized cohort of women in WIHS. Using multiparameter flow cytometry, real- time PCR and PCR array technologies, we developed platforms to systematically evaluate both immunologic and virologic factors impacting disease. We performed complex validation experiments allowing simultaneous evaluation of soluble and cellular biomarkers, molecular gene-signatures of immune activation, exhaustion, senescence and regulation, and virologic studies from one sample. Our central hypothesis is that HIV- associated immune dysregulation and HCV infection with liver dysfunction maintains this state of immune hyperactivation, leading to immune exhaustion and senescence and more rapid progression of HANA conditions, even with effective HAART. Furthermore, liver disease will play a major role in determining immunologic, virologic and clinical outcomes especially as women age and enter menopause. Our specific aims are: Specific Aim 1) Define determinants and consequences of long-term immune activation in singly and co-infected women successfully treated with HAART and Specific Aim 2) Assess gene expression patterns involved in molecular mechanisms promoting immune activation, senescence, exhaustion, and progression to clinical outcomes. For Specific Aim 1, we will longitudinally compare levels of cytokines and soluble and cellular markers of activation and immune regulation and determine impact on immune senescence/exhaustion and disease outcome. For Specific Aim 2, we will evaluate intrinsic host gene- signature pathways of immunity using real time PCR array technology and will evaluate interferon response related to immune activation, exhaustion and senescence. These studies will identify the impact of long-term activation and dysregulation on senescence and exhaustion and the role of HCV co-infection in hopes of developing treatment strategies that may prevent continued hyperactivation and the onset disease.