Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in Chimpanzees
Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in Chimpanzees
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DOI：
10.1002/hep.20239
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发表时间：
2004-06-01
期刊：
影响因子：
13.5
通讯作者：
Feinstone, SM
中科院分区：
文献类型：
--
作者：
Major, ME;Dahari, H;Feinstone, SM
为了研究 HCV 感染后临床结果的决定因素，我们对 10 只幼崽黑猩猩的病毒动力学、免疫事件和肝内细胞因子标记物进行了比较。其中四只动物清除了丙肝病毒； 6 人出现持续感染。所有动物均出现类似的急性感染，病毒血症在 1 至 2 周内逐渐增加，随后出现丙氨酸转氨酶 (ALT) 升高和血清转化。这种病毒血症模式由双相增加、快速斜率（平均倍增时间 [t(2)] = 0.5 天）和第二周后较慢的斜率（t(2) = 7.5 天）组成。在所有动物中，病毒复制的减慢与肝内 2'5' 寡腺苷酸合成酶 1 (2OAS-1) 信使 RNA (mRNA) 水平增加相关，并且与疾病结果无关。肝内干扰素 γ (IFN-γ) mRNA 和 ALT 水平增加后，观察到病毒复制得到有效控制。尽管该对照在所有动物中都与病毒滴度下降 2 个对数级相关，但在慢性组中，时间发生在大约 2 周后 (P < .05)。此外，虽然清除的感染的特点是病毒滴度持续下降，但持续感染的滴度达到了 10(4) 至 10(5) RNA 拷贝/mL 的稳态水平。在持续感染中，免疫反应无法维持病毒清除，与肝内 CD3e 和单核细胞诱导蛋白 1α (MIP-1α) mRNA 诱导减少有关。总之，这些数据表明，无论结果如何，黑猩猩都会在早期和晚期急性期产生控制 HCV 复制的反应。然而，HCV 的发病机制可能由诱导反应的更快发生和迁移至肝脏的细胞群决定。
To study determinants of clinical outcome following HCV infection, viral kinetics, immune events, and intrahepatic cytokine markers were compared in 10 naive chimpanzees. Four of the animals cleared HCV; 6 developed persistent infections. All animals developed similar acute infections with increasing viremia from 1 to 2 weeks, followed by alanine aminotransferase (ALT) elevations and seroconversion. This viremia pattern consisted of a biphasic increase, a rapid slope (mean doubling time [t(2)] = 0.5 days) followed by a slower slope after the second week (t(2) = 7.5 days). This slowing of virus replication correlated in all animals with increased intrahepatic 2'5' oligoadenylate synthetase 1 (2OAS-1) messenger RNA (mRNA) levels and was independent of disease outcome. An effective control of virus replication was observed following increases in intrahepatic interferon gamma (IFN-gamma) mRNA and ALT levels. Although this control was associated in all animals with a 2-log decrease in virus titer, the timing occurred approximately 2 weeks later in, the chronic group (P < .05). Additionally, while cleared infections were characterized by a continual decrease in virus titer, the titers in the persistent infections reached a steady state level of 10(4) to 10(5) RNA copies/mL. This inability of the immune response to sustain viral clearance in the persistent infections was associated with a reduced intrahepatic CD3e and monocyte-induced protein 1alpha (MIP-1alpha) mRNA induction. In conclusion, these data indicate that, regardless of outcome, chimpanzees generate responses that control HCV replication during the early and late acute phase. However, the pathogenesis of HCV may be determined by a more rapid onset of the induced response and the cell population that migrates to the liver.