Urbani Simona, Boni Carolina, Missale Gabriele, Elia Gianfranco, Cavallo Cristina, Massari Marco, Raimondo Giovanni, Ferrari Carlo
Divisione Malattie Infettive ed Epatologia, Azienda Ospedaliera Universitaria di Parma, Via Gramsci 14, 43100 Parma, Italy.
J Virol. 2002 Dec;76(24):12423-34. doi: 10.1128/jvi.76.24.12423-12434.2002.
Hepatitis B and hepatitis C viruses (HBV and HCV) are both noncytopathic and can cause acute and chronic infections of the liver. Although they share tropism for the same organ, development of chronic hepatitis is much more frequent following HCV infection, suggesting different mechanisms of viral persistence. In this study, we show that circulating HBV- and HCV-specific tetramer-positive CD8 cells during the acute phase of hepatitis B and C belong almost entirely to an effector-memory subset (CCR7(-) CD45RA(-)). Despite this phenotypic similarity, HBV- and HCV-specific CD8 cells show striking functional differences. HBV-specific tetramer-positive CD8 cells express high perforin content ex vivo, expand vigorously, and display efficient cytotoxic activity and gamma interferon (IFN-gamma) production upon peptide stimulation. A comparable degree of functional efficiency is maintained after the resolution of hepatitis B. In contrast, HCV-specific CD8 cells in the acute phase of hepatitis C express significantly lower levels of perforin molecules ex vivo and show depressed CD8 function in terms of proliferation, lytic activity, and IFN-gamma production, irrespective of the final outcome of the disease. This defect is transient, because HCV-specific CD8 cells can progressively improve their function in patients with self-limited hepatitis C, while the CD8 function remains persistently depressed in subjects with a chronic evolution.
乙型肝炎病毒和丙型肝炎病毒（HBV和HCV）均无细胞病变作用，均可引起肝脏的急性和慢性感染。尽管它们对同一器官具有嗜性，但丙型肝炎病毒感染后慢性肝炎的发生率要高得多，这表明病毒持续存在的机制不同。在本研究中，我们发现，在乙型和丙型肝炎急性期，循环中的HBV和HCV特异性四聚体阳性CD8细胞几乎完全属于效应记忆亚群（CCR7(-) CD45RA(-)）。尽管在表型上有相似之处，但HBV和HCV特异性CD8细胞显示出显著的功能差异。HBV特异性四聚体阳性CD8细胞在体外表达高水平的穿孔素，能强烈扩增，在肽刺激后表现出高效的细胞毒性活性和γ干扰素（IFN-γ）产生。乙型肝炎消退后仍维持相当程度的功能效率。相比之下，丙型肝炎急性期的HCV特异性CD8细胞在体外表达的穿孔素分子水平显著较低，并且在增殖、裂解活性和IFN-γ产生方面表现出CD8功能低下，与疾病的最终结局无关。这种缺陷是短暂的，因为HCV特异性CD8细胞在自限性丙型肝炎患者中可逐渐改善其功能，而在慢性进展的患者中CD8功能仍持续低下。
