Viral And Immune Factors That Influence Recovery Or Progression Of Hepatitis C

影响丙型肝炎恢复或进展的病毒和免疫因素

基本信息

批准号：
7733560
负责人：
HARVEY J ALTER
金额：
$ 3.94万
依托单位：
CLINICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Approximately 15 percent of patients recover from hepatitis C virus (HCV) infection while 85 percent become persistently infected with various degrees of associated chronic liver disease. In this study, comparisons will be made between patients who rapidly recover, those who have delayed recovery, those with persistent infection and stable chronic disease and those with rapidly progressive, fatal infection. The parameters measured will be viral burden (initially and over time), HCV genotype, the number of viral quasi-species (extent of viral heterogeneity) at the time of infection and subsequently, neutralizing antibody responses and, T-cell helper, proliferative and cytotoxic responses. The goal is to determine if any of these parameters can predict outcome. Studies to date have shown no correlation with genotype since the population is fairly homogeneous for HCV genotype 1. However, there does appear to be a correlation between viral quasi-species and disease outcome. Using rare specimens obtained during the first 16 weeks of HCV infection, we have measured the mean Hamming distance that reflects the extent of viral diversity (the degree of sequence divergence within the viral quasi-species). We have found that the mean Hamming distance 12 to 16 weeks after the onset of acute infection predicts whether the patient will recover from HCV infection or develop persistent infection and chronic liver disease. Patients who recover have a declining Hamming distance as antibody to HCV develops, signifying immunologic containment and then clearance of the virus. In contrast, the majority of patients demonstrate an increased mean hamming distance as antibody appears. This suggests that if the immune response is not sufficient to clear the virus, it paradoxically exerts immune pressure that results in mutations (escape variants) that lead to persistent infection. Interestingly, patients with fulminant hepatitis have a very low degree of viral diversity because they succumb to the infection before the immune system can clear the virus or exert immune pressure. This study has been published (Science 288:339-344.2000). In the current study, we are measuring the quasi-species throughout the long-term course of HCV infection and the relation of the quasispecies to treatment responses.In addition we will identify patients with newly acquired or newly recognized hepatitis C so that we can serially measure viral load, viral quasi-species, neutralizing antibody responses and particularly, cell-mediated immune responses. Thus far, studies have shown that patients with chronic HCV infection have impaired CD4 and CD8 cell responses to all HCV antigens compared to patients who recover from acute HCV infection.We have also found that neutralizing antibodies do not correlate with recovery from acute HCV infection, but rather continue to increase in strength and breath of activity over the course of chronic infection. Despite these antibodies, escape mutants continue to evade the immune response.

大约15％的患者从丙型肝炎病毒（HCV）感染中康复，而85％的患者持续感染了各种程度的相关慢性肝病。在这项研究中，将与迅速康复的患者，康复延迟的患者，患有持续感染和稳定慢性疾病的患者以及患有快速进行性致命感染的患者进行比较。所测量的参数将是病毒负担（最初和随着时间的推移），HCV基因型，感染时病毒准物种（病毒异质性的程度）的数量以及随后中和抗体反应的中和，T-cell Helper，T-Cellper，增殖性和细胞毒性反应。目标是确定这些参数中的任何一个都可以预测结果。迄今为止的研究表明，由于HCV基因型1的种群相当均匀，因此与基因型没有相关性。但是，病毒准物种与疾病结果之间似乎确实存在相关性。使用在HCV感染的前16周获得的稀有标本，我们测量了反映病毒多样性程度（病毒准物种内序列差异程度）的平均锤距。我们发现，急性感染发作后12至16周的平均锤距距离预测患者是从HCV感染中恢复还是发展持续性感染和慢性肝病。随着HCV抗体的发展，康复距离的恢复距离下降，表示免疫抑制，然后清除病毒。相比之下，大多数患者显示出抗体出现的平均锤距距离增加。这表明，如果免疫反应不足以清除病毒，则自相矛盾地施加免疫压力，从而导致突变（逃生变体）导致持续感染。有趣的是，暴发性肝炎患者的病毒多样性程度很低，因为在免疫系统可以清除病毒或施加免疫压力之前，它们会屈服于感染。这项研究已发表（科学288：339-344.2000）。在当前的研究中，我们正在整个HCV感染的长期过程中测量准物种以及准菜与治疗反应的关系。此外，我们将确定具有新近获得或新认识的乙型肝炎或新认识的乙型肝炎的患者，以便我们可以连续测量病毒载荷，病毒式质量反应，中上述抗体特异性，中性抗体抗体反应，尤其是细胞疾病，尤其是细胞相关的疾病。迄今为止，研究表明，与从急性HCV感染中恢复的患者相比，患有慢性HCV感染的患者对所有HCV抗原的CD4和CD8细胞反应受损。我们还发现，中和的抗体与急性HCV感染的恢复无关，而是继续增加了运动的强度和呼吸，超出了运动的强度和呼吸。尽管有这些抗体，但逃生突变体继续逃避免疫反应。