Interactions Between HIV and HCV in 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)，80%的人仍然长期感染这种病原体。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。尽管血友病人群是独一无二的，但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。HGDS在1989-1990年间招募了333名血友病患者，并对他们进行了7-8年的跟踪调查。这项多中心的美国研究代表了一个具有良好特征的、前瞻性跟踪的丙型肝炎病毒感染血友病患者队列，其中207人是HIV-1共同感染者。然而，目前尚不清楚丙型肝炎病毒混合感染如何影响HIV-1的自然发展史。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。HIV和HCVRNA水平用第二代CHIRON BDNA测定仪进行定量。不出所料，我们发现艾滋病毒感染儿童的基线HCVRNA高于未感染组(p=0.0001)。CD4+T细胞绝对值与HIV病毒载量呈正相关，与HIV病毒载量呈正相关，与HIV病毒载量呈正相关。我们发现丙型肝炎病毒载量和进展到艾滋病的速度之间有显著的相关性：在控制了HIV RNA、CD4+T细胞和抗病毒治疗后，基线的丙型肝炎病毒RNA每增加10倍，进展到艾滋病的相对风险就增加1.60。我们还观察到，在感染艾滋病毒的儿童中，丙型肝炎病毒清除率明显较低。这项研究表明，丙型肝炎病毒是HIV临床进展的独立预测因子，并建议在合并感染的患者中研究降低丙型肝炎病毒载量的治疗干预措施。 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。这些将被分析与对病毒多肽的特定免疫反应之间的关联。

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 by this agent. 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. Although the hemophiliac population is unique, co-infection by these chronic viral pathogens is becoming increasingly common, particularly amongst 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 between 1989 and 1990 and followed them for 7-8 years. This multicenter, United States study represents a well-characterized, prospectively followed cohort of HCV-infected hemophiliacs, of whom 207 are HIV-1 co-infected. However, it was not known how HCV coinfection affects the natural history of HIV-1 progression. 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. HIV and HCV RNA levels were quantified using second generation Chiron bDNA assays. Not unexpectedly, we found that baseline HCV RNA was higher in HIV-infected children than in uninfected groups (p=0.0001). There were significant correlations between baseline CD4+ cell number, HIV RNA and HCV RNA: higher absolute CD4+ T cells were correlated with lower HCV RNA while higher HCV RNA was strongly correlated with high HIV viral load. We found a significant association between HCV viral load and rate of progression to AIDS: after controlling for HIV RNA, CD4+ T cells, and antiviral therapy, for every 10-fold increase in baseline HCV RNA, there was a 1.60 increase in the relative hazard for progression to AIDS. We also observed that HCV clearance rates are significantly lower in children with HIV coinfection. This study demonstrates that HCV is an independent predictor of HIV clinical progression and suggests that therapeutic interventions to lower HCV viral load should be investigated in coinfected patients. 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 differention 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 associations with specific immune responses to viral peptides.