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年之前接受未经热处理的凝血因子浓缩物。此外，这些人普遍感染丙型肝炎病毒（HCV），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史的重要人群。此外，合并感染的高比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应答与临床进展之间的关系的理想组。这些慢性病毒病原体的合并感染变得越来越普遍，特别是在静脉注射吸毒者中，他们占美国流行病的约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，调查了与HIV-1和HCV免疫发病机制相关的问题。HGDS在1989年至1990年期间招募了333名血友病患者，其中207人是HIV-1合并感染者，并对他们进行了7-8年的随访。共有332名血友病患者在基线和7年随访期间每年重复检测1-8次HCV RNA。每年测量所有受试者的CD 4+细胞和血浆HCV RNA，每年测量HIV感染受试者的血浆HIV RNA。我们以前曾报道，高HCV病毒载量与HIV-1合并感染的血友病患者的发病率和死亡率增加有关，HIV-1感染与持续HCV感染的风险增加有关。 我们现在正在研究病毒特异性免疫反应在控制HIV-1和HCV复制中的作用，以及这些反应如何受到免疫系统的调节。影响T细胞分化的遗传多态性可能影响Th 1/Th 2平衡和免疫系统对特定HIV-1和HCV表位的细胞毒性反应的有效性。我们已经确定了单核苷酸多态性的调节或非编码区的细胞因子已知有一个作用，在确定Th 1/Th 2状态。将分析这些与HCV和/或HIV病毒肽的细胞毒性T淋巴细胞（CTL）免疫应答的强度和呼吸的相关性。我们已经完成了整个HGDS队列的HCV基因分型，现在正在研究HCV基因型对HIV-1临床进展为AIDS和HIV-1 RNA水平的作用。 我们对100多个基因的单核苷酸多态性（SNP）进行了完整的基因分型，包括APOBEC 3G和TRIM 5，这些基因参与免疫调节，病毒进入和病毒生命周期的成功完成。HIV-1趋化因子共受体及其配体中的宿主遗传变异已显示通过改变表面表达和用于HIV-1结合的共受体的可用性来改变HIV-1进展的速率。然而，它们对HIV-1病毒载量的影响尚不明确。我们已经测试了100多个SNP对HCV清除的影响，并确定了几种影响清除的免疫应答调节剂。通过限制病毒复制来影响HIV或HCV发病机制的遗传因素的鉴定可以为潜在的治疗干预提供靶点，或者为CTL成功免疫调节所涉及的因素提供线索。

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.