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

大约15%的患者从丙型肝炎病毒（HCV）感染中恢复，而85%的患者持续感染不同程度的相关慢性肝病。在这项研究中，将比较快速恢复的患者、延迟恢复的患者、持续感染和稳定慢性疾病的患者以及快速进展、致命感染的患者。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、感染时和随后的中和抗体反应、t细胞辅助反应、增殖反应和细胞毒性反应的病毒准种数量（病毒异质性程度）。目的是确定这些参数是否可以预测结果。迄今为止的研究显示与基因型没有相关性，因为HCV基因型1的人群相当均匀。然而，病毒准种与疾病结果之间确实存在相关性。使用HCV感染前16周获得的罕见标本，我们测量了反映病毒多样性程度的平均汉明距离（病毒准种内序列差异的程度）。我们发现，急性感染发生后12 ~ 16周的平均汉明距离可以预测患者是否会从HCV感染中恢复或发展为持续感染和慢性肝病。随着HCV抗体的产生，康复的患者汉明距离下降，这意味着免疫控制和病毒清除。相反，当抗体出现时，大多数患者的平均汉明距离增加。这表明，如果免疫反应不足以清除病毒，它会矛盾地施加免疫压力，导致突变（逃逸变异），从而导致持续感染。有趣的是，暴发性肝炎患者的病毒多样性程度非常低，因为他们在免疫系统清除病毒或施加免疫压力之前就被感染了。这项研究发表在2000年的《科学》杂志上（通过病毒准物种的进化预测急性丙型肝炎的结局；Science 288:339-344）。

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 on Science in 2000(The outcome of acute hepatitis C predicted by the evolution of the viral quasi-species; Science 288:339-344). In ongoing studies, we are measuring the viral quasi-species throughout the long-term course of HCV infection and the relation of the quasispecies other parameters to the outcome of HCV infection. 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. Most recently, we have compared patients who have severe, rapidly progressive hepatitis C to those who have a stable indolent course. We found that patients with rapid progression have a delayed or impaired immunologic response to HCV, an inability to reduce viral load early in infection, a greater degree of viral diversity, a diminished interferon response and, importantly, an early and sustained elevation of the pro-fibrogenic cytokine, MCP-1. We are now testing in a larger cohort whether MCP-1 could serve as a predictive marker of severe fibrosis in patients with chronic hepatitis C. Ongoing studies are looking for other cytokines or micro RNAs that might predict fibrosis progression. In this regard we have shown that the miRNA, Let-7, is a predictive marker of fibrosis progression. . Let-7 is a suppressor of TGF-, a primary activator of hepatic stellate cells that induce hepatic fibrosis. When Let-7 levels diminish, TGF- is freed to activate stellate cells leading to progressive fibrosis and ultimately cirrhosis. In another study in collaboration with Patricia Farci of NIAID, we have shown that a chemokine chitinase-3 (CHI3L1) increases in the aging liver and serves to activate hepatic stellate cells. This establishes an autocrine loop wherein the stellate cells are activated and produce more chitinase-3. The net result is that as the stellate cells are activated they lay down collagen and incite liver fibrosis progression in a manner similar to that which occurs when Let-7 is suppressed and activates TGF-. These factors help to explain the progressive fibrosis that occurs in 20%-30% of patients with chronic hepatitis C and suggests possible therapeutic avenues to reverse these processes. The following Nobel Prize Lectures are associated with this research. 1-Alter HJ. Nobel Lecture: Hepatitis C Virus: From Hippocrates to Cure in Nobel Prize Lectures 2020 2-Alter HJ. Nobel Autobiography: I Never Had No Nobel Dreams in Nobel Prize Lectures 2020