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)感染中康复，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，将对康复迅速的患者、恢复延迟的患者、持续感染和稳定的慢性病患者以及快速进展的致命感染患者进行比较。测量的参数将是病毒载量(最初和随着时间的推移)、丙型肝炎病毒基因型、感染时病毒准物种的数量(病毒异质性的程度)以及随后的中和抗体反应和T细胞辅助反应、增殖和细胞毒性反应。我们的目标是确定这些参数中是否有任何一个可以预测结果。到目前为止，研究还没有显示出与基因型的相关性，因为人群中的丙型肝炎病毒基因1型是相当同质的。然而，似乎在病毒准物种和疾病结果之间确实存在相关性。使用在丙型肝炎病毒感染的前16周内获得的稀有标本，我们测量了反映病毒多样性程度(病毒准物种内的序列差异程度)的平均汉明距离。我们发现，急性感染发作后12到16周的平均Hamming距离预测患者是否会从丙型肝炎病毒感染中恢复，或者发展为持续性感染和慢性肝病。随着丙型肝炎病毒抗体的产生，康复患者的汉明距离不断下降，这意味着免疫抑制，然后病毒被清除。相反，大多数患者的平均Hamming距离随着抗体的出现而增加。这表明，如果免疫反应不足以清除病毒，它就会矛盾地施加免疫压力，导致突变(逃逸变体)，从而导致持续感染。有趣的是，重型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死于感染。这项研究发表在2000年的《科学》上(通过病毒准物种的进化预测急性丙型肝炎的结果；科学288：339-344)。 在正在进行的研究中，我们正在测量丙型肝炎病毒感染长期过程中的病毒准种，以及准种和其他参数与丙型肝炎病毒感染结局的关系。到目前为止，研究表明，与急性丙型肝炎病毒感染恢复的患者相比，慢性丙型肝炎病毒感染者对所有丙型肝炎病毒抗原的CD4和CD8细胞反应受损。我们还发现，中和抗体与急性丙型肝炎病毒感染的康复无关，而是在慢性感染过程中继续增加强度和活动呼吸。尽管有这些抗体，逃逸突变体仍继续逃避免疫反应。最近，我们比较了患有严重、进展迅速的丙型肝炎的患者和那些病程稳定、无痛的患者。我们发现，进展迅速的患者对丙型肝炎病毒的免疫反应延迟或受损，无法在感染早期减少病毒载量，病毒多样性程度更高，干扰素反应减弱，更重要的是，促纤维化细胞因子MCP-1早期和持续升高。我们现在正在一项更大的队列中测试MCP-1是否可以作为慢性丙型肝炎患者严重纤维化的预测标志。 正在进行的研究正在寻找其他可能预测纤维化进展的细胞因子或微型RNA。在这方面，我们已经证明了miRNA，let-7，是纤维化进展的预测标记物。。Let-7是一种转化生长因子-7的抑制因子，转化生长因子-7是导致肝纤维化的肝星状细胞的主要激活剂。当let-7水平降低时，转化生长因子-7被释放，激活星状细胞，导致进行性纤维化，最终导致肝硬变。在与NIAID的Patricia Farci合作的另一项研究中，我们发现趋化因子几丁质酶-3(CHI3L1)在老化的肝脏中增加，并用于激活肝星状细胞。这建立了一个自分泌环路，其中星状细胞被激活并产生更多的几丁质酶-3。最终的结果是，当星状细胞被激活时，它们沉积胶原蛋白并刺激肝纤维化进展，其方式类似于抑制并激活转化生长因子-7时发生的情况。这些因素有助于解释在20%-30%的慢性丙型肝炎患者中发生的进行性纤维化，并提出了逆转这些过程的可能的治疗途径。 以下是与这项研究有关的诺贝尔奖演讲。 1-更改HJ。2020年诺贝尔奖演讲：丙型肝炎病毒：从希波克拉底到治愈 2-更改HJ。诺贝尔奖自传：我在2020年的诺贝尔奖演讲中从未有过诺贝尔奖梦想

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