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，将对快速恢复的患者、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的致命性感染的患者进行比较。测量的参数将是病毒负荷（初始和随时间推移）、HCV基因型、感染时的病毒准种数（病毒异质性程度）以及随后的中和抗体应答和T辅助细胞、增殖和细胞毒性应答。我们的目标是确定这些参数中的任何一个是否可以预测结果。迄今为止的研究表明，没有相关性与基因型，因为人口是相当同质的HCV基因型1。然而，病毒准种和疾病结果之间似乎确实存在相关性。使用在HCV感染的前16周获得的罕见标本，我们测量了平均汉明距离，反映了病毒多样性的程度（病毒准种内的序列差异程度）。我们发现，急性感染发作后12至16周的平均汉明距离可预测患者是否会从HCV感染中恢复或发展为持续感染和慢性肝病。恢复的患者随着HCV抗体的发展而具有下降的汉明距离，这意味着免疫遏制，然后清除病毒。相比之下，大多数患者显示抗体出现时平均汉明距离增加。这表明，如果免疫反应不足以清除病毒，它会自相矛盾地施加免疫压力，导致突变（逃逸变体），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。这项研究已于2000年发表在《科学》杂志上（《病毒准种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，我们正在测量整个HCV感染的长期过程中的病毒准种，以及准种其他参数与HCV感染结果的关系。迄今为止，研究表明，与从急性HCV感染中恢复的患者相比，慢性HCV感染患者对所有HCV抗原的CD 4和CD 8细胞应答受损。我们还发现，中和抗体与急性HCV感染的恢复无关，而是在慢性感染过程中继续增加活性的强度和呼吸。尽管有这些抗体，逃避突变体继续逃避免疫反应。最近，我们比较了严重的、快速进展的丙型肝炎患者和那些有稳定的惰性病程的患者。我们发现，快速进展的患者对HCV的免疫应答延迟或受损，无法在感染早期降低病毒载量，病毒多样性程度更高，干扰素应答降低，重要的是，促纤维化细胞因子MCP-1的早期和持续升高。我们现在正在一个更大的队列中测试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物。 正在进行的研究正在寻找可能预测纤维化进展的其他细胞因子或微RNA。在这方面，我们已经表明，miRNA Let-7是纤维化进展的预测标志物。. Let-7是TGF-β的抑制剂，TGF-β是诱导肝纤维化的肝星状细胞的主要激活剂。当Let-7水平降低时，TGF-β被释放以激活星状细胞，导致进行性纤维化和最终肝硬化。在与NIAID的Patricia Farci合作的另一项研究中，我们已经表明趋化因子几丁质酶-3（CHI 3L 1）在衰老的肝脏中增加，并用于激活肝星状细胞。这建立了一个自分泌回路，其中星状细胞被激活并产生更多的几丁质酶-3。最终结果是，当星状细胞被激活时，它们沉积胶原蛋白并以类似于Let-7被抑制并激活TGF-β时发生的方式刺激肝纤维化进展。这些因素有助于解释20%-30%的慢性丙型肝炎患者发生的进行性纤维化，并提出了逆转这些过程的可能治疗途径。 以下诺贝尔奖演讲与这项研究有关。 1-改变HJ。2020年诺贝尔奖讲座：丙型肝炎病毒：从希波克拉底到治愈 2-改变HJ。诺贝尔自传：2020年诺贝尔奖讲座中我从未没有诺贝尔梦

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