HCV and HIV Progression in Women on HAART

描述(由申请者提供)：概述：虽然有共识认为艾滋病毒会加速混合感染(艾滋病毒+丙型肝炎+)患者的丙型肝炎(丙型肝炎)疾病，但关于丙型肝炎病毒感染对艾滋病毒疾病进展的影响，研究存在分歧。这项提案寻求继续支持我们的赠款、丙型肝炎病毒以及艾滋病毒和HAART在妇女中的反应进展。在过去的5年中，我们发现丙型肝炎病毒加速了HIV疾病的进展，这与双重病毒感染导致的免疫激活和T细胞成熟改变有关。我们的中心假设是，由于丙型肝炎病毒动力学的结果，艾滋病毒疾病的进展受到增强的CD8激活和改变的T细胞成熟的影响，并且在正在进行的丙型肝炎病毒复制的背景下，HAART不会完全逆转这一点。具体目的：1)确定丙型肝炎病毒感染者外周血中丙型肝炎病毒的肝外复制、丙型肝炎病毒动态与HIV疾病进展之间的关系。2)纵向研究T细胞活化/成熟与功能的关系，以及a)丙型肝炎病毒准种动态与肝外贮备库的关系。B)疾病进展。3)评估HIV病毒载量应答(VLR)和HAART后反弹与PBMC中的丙型肝炎病毒蓄积量和丙型肝炎病毒准种动态的关系。4)确定免疫激活和T细胞成熟/功能与HAART后HIV VLR和反弹的关系，以及与肝外复制和准种多样性的关系。临床意义：到目前为止，我们的研究发现，与单独感染的女性相比，合并感染的女性发生艾滋病的可能性几乎是单独感染的女性的两倍；b)在较低的HIV RNA水平下，艾滋病和死亡的相对风险(RH)增加；c)与激活的CD8+T细胞水平较高相关的艾滋病相对风险增加；d)与饮酒和既往艾滋病相关的PBMC中丙型肝炎病毒复制的患病率增加40%；以及，e)活跃的IDU中丙型肝炎病毒准种的变化增加3倍。这些发现支持了我们的假设，即丙型肝炎病毒动力学有助于免疫失调和艾滋病的发展以及艾滋病相关死亡。合并感染的妇女可能需要在比目前建议的更低的艾滋病毒RNA和更高的CD4计数阈值下开始抗逆转录病毒治疗(ART)，以预防艾滋病/死亡。考虑到与艾滋病毒疾病进展相关的许多临床、人口和行为特征，需要一个大的队列。这项拟议的研究将使我们能够更好地定义那些可能从更具侵袭性的抗逆转录病毒疗法中受益的人。在这项研究中，我们将确定外周PBMC中的丙型肝炎病毒复制、丙型肝炎病毒动态和a)艾滋病毒疾病进展；b)妇女机构间艾滋病毒研究中艾滋病毒感染者以及艾滋病毒和丙型肝炎联合感染妇女中对HAART的长期反应之间的关系。此外，我们将纵向研究T细胞的激活/成熟和功能与a)丙型肝炎病毒准种动态和肝外贮存库以及b)HIV疾病进展的关系。

DESCRIPTION (provided by applicant): Overview: Although there is consensus that HIV accelerates hepatitis C (HCV) disease in co-infected (HIV+HCV+) patients, studies differ regarding the impact of HCV infection on HIV disease progression. This proposal seeks continued support for our grant HCV and Progression of HIV and HAART Response in Women . During the past 5 years we found that HCV accelerates HIV disease progression and that this is related to immune activation and altered T cell maturation as a result of dual viral infection. Our central hypothesis is that HIV disease progression is impacted by enhanced CD8 activation and altered T cell maturation as a result of HCV viral dynamics and that HAART will not completely reverse this in the setting of ongoing HCV replication. Specific Aims: 1) Determine the relationships among extrahepatic replication of HCV in PBMC, HCV dynamics and HIV disease progression in co-infected HCV viremic women. 2) Longitudinally investigate the relationship of T cell activation/maturation and function and a) HCV quasispecies dynamics and extrahepatic reservoirs. b) Disease progression. 3) Assess the relationship of HCV reservoirs in PBMC and HCV quasispecies dynamics with HIV viral load response (VLR) and rebound post-HAART. 4) Determine the relationship of immune activation and T cell maturation/function with HIV VLR and rebound post-HAART and correlate with extrahepatic replication and quasispecies diversity. Clinical Significance: Our studies thus far find that compared with singly infected women, co-infected women had: a) an almost two-fold increased probability of developing AIDS among women who never had CD4 counts < 200 cells/mm3; b) an increased relative hazard (RH) of AIDS and death at lower HIV RNA levels; c) increased RH of AIDS associated with higher levels of activated CD8+ T cells; they also had d) a 40% prevalence of HCV replication in PBMC which was associated with alcohol use and prior AIDS; and, e) a 3 fold increase in changes in HCV quasispecies among active IDU. These findings support our hypothesis that HCV dynamics contributes to immune dysregulation and the development of AIDS and AIDS-related death. Co- infected women may need to initiate antiretroviral treatment (ART) at lower HIV RNA and higher CD4 count thresholds than is currently recommended, to prevent AIDS/death. Given the many clinical, demographic and behavioral characteristics associated with HIV disease progression, a large cohort is needed. The proposed study will allow us to better define those who may benefit from more aggressive ART.In this study we will determine the relationships among extrahepatic HCV replication in PBMC, HCV dynamics and a) HIV disease progression; b) long-term response to HAART among HIV infected and HIV and HCV co- infected women from the Women's Interagency HIV Study. Further, we will longitudinally investigate the relationship of T cell activation/maturation and function with a) HCV quasispecies dynamics and extrahepatic reservoirs and b) HIV disease progression.