CYTOTOXIC T-LYMPHOCYTES INHIBIT HEPATITIS-B VIRUS GENE-EXPRESSION BY A NONCYTOLYTIC MECHANISM IN TRANSGENIC MICE
CYTOTOXIC T-LYMPHOCYTES INHIBIT HEPATITIS-B VIRUS GENE-EXPRESSION BY A NONCYTOLYTIC MECHANISM IN TRANSGENIC MICE
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DOI：
10.1073/pnas.91.9.3764
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发表时间：
1994-04-26
影响因子：
11.1
通讯作者：
CHISARI, FV
中科院分区：
文献类型：
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作者：
GUIDOTTI, LG;ANDO, K;CHISARI, FV
在B型肝炎病毒（HBV）感染过程中，不同的宿主-病毒相互作用可确定病毒清除和持续的模式以及病毒相关病理的程度。一般认为，HBV特异性I类限制性细胞毒性T淋巴细胞（CTL）通过破坏感染的肝细胞在这一过程中发挥关键作用。然而，如果大多数肝细胞被感染，这种细胞病变机制可能是致命的。在目前的研究中，我们证明，I类限制性HBV特异性CTL深刻抑制HBV转基因小鼠肝细胞HBV基因表达的noncytolytic过程，其强度大大超过了CTLs的细胞病变的影响的幅度和持续时间。我们还表明，CTL的调节作用最初是由干扰素γ和肿瘤坏死因子α介导的，延迟发作，并在开始后不久就变得独立于这些细胞因子。这些数据表明，抗病毒CTL应答激活了一个复杂的调节级联反应，该级联反应抑制肝细胞HBV基因表达而不杀死细胞。在HBV感染期间，这种机制在多大程度上有助于病毒清除或病毒持续存在仍有待确定。
During hepatitis B virus (HBV) infection, distinct host-virus interactions may establish the patterns of viral clearance and persistence and the extent of virus-associated pathology. It is generally thought that HBV-specific class I-restricted cytotoxic T lymphocytes (CTLs) play a critical role in this process by destroying infected hepatocytes. This cytopathic mechanism, however, could be lethal if most of the hepatocytes are infected. In the current study, we demonstrate that class I-restricted HBV-specific CTLs profoundly suppress hepatocellular HBV gene expression in HBV transgenic mice by a noncytolytic process, the strength of which greatly exceeds the cytopathic effect of the CTLs in magnitude and duration. We also show that the regulatory effect of the CTLs is initially mediated by interferon gamma and tumor necrosis factor alpha, is delayed in onset, and becomes independent of these cytokines shortly after it begins. The data indicate that the anti-viral CTL response activates a complex regulatory cascade that inhibits hepatocellular HBV gene expression without killing the cell. The extent to which this mechanism contributes to viral clearance or viral persistence during HBV infection remains to be determined.