HCV and HIV Progression in Women on HAART

概述：虽然在合并感染（HIV+HCV+）患者中，HIV加速丙型肝炎（HCV）的发展是共识，但关于HCV感染对HIV疾病进展的影响，研究存在差异。该提案寻求继续支持我们的资助HCV和妇女艾滋病病毒进展和HAART反应。在过去的5年中，我们发现HCV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HCV病毒动力学，HIV疾病进展受到CD8激活增强和T细胞成熟改变的影响，并且在HCV持续复制的情况下，HAART不会完全逆转这一点。具体目的：1)确定HCV在PBMC中肝外复制、HCV动力学与合并感染HCV病毒血症妇女HIV疾病进展的关系。2)纵向研究T细胞活化/成熟与功能的关系；a) HCV准种动力学与肝外储库的关系。b)疾病进展。3)评估PBMC中HCV储存库和HCV准种动态与haart后HIV病毒载量反应（VLR）和反弹的关系。4)确定免疫激活和T细胞成熟/功能与HIV VLR和haart后反弹的关系，并与肝外复制和准物种多样性相关。临床意义：迄今为止，我们的研究发现，与单一感染妇女相比，合并感染妇女有：a)在CD4细胞计数从未< 200细胞/mm3的妇女中，发生艾滋病的可能性几乎增加了两倍；b)艾滋病毒RNA水平较低时，艾滋病和死亡的相对危险度（RH）增加；c)艾滋病RH升高与CD8+ T细胞活化水平升高相关；d) PBMC中HCV复制的患病率为40%，这与酒精使用和既往艾滋病有关；e)在有效IDU中HCV准种的变化增加了3倍。这些发现支持了我们的假设，即HCV动力学有助于免疫失调和艾滋病的发展和艾滋病相关死亡。为了预防艾滋病/死亡，合并感染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计数阈值时开始抗逆转录病毒治疗（ART）。鉴于与艾滋病毒疾病进展相关的许多临床、人口统计学和行为特征，需要进行大规模队列研究。拟议的研究将使我们能够更好地确定哪些人可能从更积极的抗逆转录病毒治疗中受益。在这项研究中，我们将确定PBMC中肝外HCV复制、HCV动力学和a) HIV疾病进展之间的关系；b)来自妇女机构间艾滋病毒研究的艾滋病毒感染者和艾滋病毒和丙型肝炎病毒共感染妇女对HAART的长期反应。此外，我们将纵向研究T细胞活化/成熟和功能与a) HCV准种动力学和肝外储存库以及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.