Interactions Between HIV/HCV in Coinfected Hemophiliacs

人类免疫缺陷病毒1型(HIV-1)经常感染血友病患者，他们在1985年之前接受了未经热处理的凝血因子浓缩物。此外，这些人普遍感染了丙型肝炎病毒(丙型肝炎病毒)，其中80%仍为慢性感染。因此，血友病患者是研究这些慢性病毒感染自然病史的重要人群。此外，高混合感染率使其成为评估病毒之间的相互作用以及病毒特异性免疫反应与临床进展之间关系的理想组别。这些慢性病毒病原体的混合感染正变得越来越普遍，特别是在静脉注射吸毒者中，他们约占美国疫情的25%。 我们通过研究参加血友病生长发育研究(HGDS)的儿童和青少年，研究了与HIV-1和丙型肝炎病毒免疫致病相关的问题。血友病中心在至1990年期间招募了333名血友病患者，其中207人为HIV-1混合感染者，并对他们进行了7-8年的跟踪调查。共有332名血友病患者在基线和7年随访期间每年重复进行1-8次丙型肝炎病毒核糖核酸检测。所有受试者每年检测CD4+细胞和血浆丙型肝炎病毒核糖核酸，HIV感染者每年检测血浆HIV核糖核酸。我们以前已经报道过，在HIV-1合并感染的血友病患者中，高的丙型肝炎病毒载量与增加的发病率和死亡率相关，并且HIV-1感染与持续性丙型肝炎病毒感染的风险增加相关。 我们现在正在研究病毒特异性免疫反应在控制艾滋病毒-1和丙型肝炎病毒复制中的作用，以及免疫系统如何调节这些反应。影响T细胞分化的基因多态可能会影响Th1/Th2平衡和免疫系统对特定HIV-1和丙型肝炎病毒表位的细胞毒反应的有效性。我们已经确定了细胞因子调节区或非编码区的单核苷酸多态，已知在决定Th1/Th2状态中起作用。这些将被分析与细胞毒性T淋巴细胞(CTL)对丙型肝炎病毒和/或HIV病毒多肽的免疫反应的强度和呼吸的相关性。我们已经完成了整个HGDS队列的丙型肝炎病毒基因分型，现在正在研究丙型肝炎病毒基因在HIV-1临床进展为艾滋病和HIV-1RNA水平上的作用。 我们对包括APOBEC3G和TRIM5在内的100多个基因的单核苷酸多态(SNPs)进行了完整的基因分型，这些基因与免疫调节、病毒进入和病毒生命周期的成功完成有关。宿主在HIV-1趋化因子辅助受体及其配体中的遗传变异已被证明通过改变HIV-1结合的辅助受体的表面表达和可用性来改变HIV-1的进展速度。然而，它们对HIV-1病毒载量的影响还不是很清楚。我们已经测试了100多个SNPs对丙型肝炎病毒清除的影响，并确定了几个影响清除的免疫反应修饰物。通过限制病毒复制来识别影响HIV或丙型肝炎病毒致病的遗传因素，可能为潜在的治疗干预提供靶点，或为CTL成功的免疫调节因素提供线索。

The human immunodeficiency virus type 1 (HIV-1) frequently infected hemophiliacs who received non-heat-treated clotting factor concentrates prior to 1985. In addition, these individuals were universally infected by hepatitis C virus (HCV) with >80% remaining chronically infected. Thus, hemophiliacs represent an important population for studies of the natural history of these chronic viral infections. Moreover, the high rate of co-infection makes it an ideal group for assessing the interaction between the viruses and the relationship between viral-specific immune responses and clinical progression. Co-infection by these chronic viral pathogens is becoming increasingly common, particularly among intravenous drug users, who account for approximately 25% of the epidemic in the United States. We have investigated issues related to HIV-1 and HCV immunopathogenesis by studying children and adolescents enrolled in the Hemophilia Growth and Development Study (HGDS). The HGDS enrolled 333 hemophiliacs of whom 207 are HIV-1 co-infected, between 1989 and 1990 and followed them for 7-8 years. A total of 332 hemophiliacs had 1-8 repeated annual HCV RNA measurements between baseline and 7 years of follow-up. CD4+ cells and plasma HCV RNA were measured annually in all subjects, and plasma HIV RNA was measured annually in the HIV-infected subjects. We have previously reported that high HCV viral load was associated with increased morbidity and mortality in HIV-1 co-infected hemophiliacs and that HIV-1 infection was associated with increased risk of persistent HCV infection. We are now investigating the role of viral-specific immunologic responses in controlling HIV-1 and HCV replication and how these responses are regulated by the immune system. Genetic polymorphisms that affect T cell differentiation may influence Th1/Th2 balance and the effectiveness of the immune system in mounting a cytotoxic response to specific HIV-1 and HCV epitopes. We have identified single nucleotide polymorphisms in regulatory or noncoding regions of cytokines known to have a role in determining Th1/Th2 states. These will be analyzed for correlations with the strength and breath of cytotoxic T lymphocytes (CTL) immune responses to HCV and/or HIV viral peptides. We have completed HCV genotyping on the entire HGDS cohort and are now investigating the role of HCV genotype on HIV-1 clinical progression to AIDS and on HIV-1 RNA levels. We have complete genotyping for single nucleotide polymorphisms (SNPs) in more than 100 genes, including APOBEC3G and TRIM5, that are involved in immune regulation, viral entry, and the successful completion of the viral life cycle. Host genetic variation in HIV-1 chemokine co-receptors and their ligands have been shown to modify rates of HIV-1 progression by altering surface expression and availability of co-receptors for HIV-1 binding. However, their influence on HIV-1 viral load is less well defined. We have tested the effects of more than 100 SNPs on HCV clearance and have identified several immune response modifiers that influence clearance. The identification of genetic factors that influence HIV or HCV pathogenesis by restricting viral replication may provide targets for potential therapeutic intervention or provide clues to factors involved in successful immune regulation by CTLs.