McClary H, Koch R, Chisari F V, Guidotti L G
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
J Virol. 2000 Mar;74(5):2255-64. doi: 10.1128/jvi.74.5.2255-2264.2000.
We have previously shown that hepatitis B virus (HBV) replication is inhibited noncytopathically in the livers of transgenic mice following injection of HBV-specific cytotoxic T lymphocytes (CTLs) or infection with unrelated hepatotropic viruses, including lymphocytic choriomeningitis virus (LCMV) and adenovirus. These effects are mediated by gamma interferon (IFNgamma), tumor necrosis factor alpha (TNFalpha), and IFNalpha/beta. In the present study, we crossed HBV transgenic mice with mice genetically deficient for IFNgamma (IFNgammaKO), the TNFalpha receptor (TNFalphaRKO), or the IFNalpha/beta receptor (IFNalpha/betaRKO) in order to determine the relative contribution of each cytokine to the antiviral effects observed in each of these systems. Interestingly, we showed that HBV replicates in unmanipulated IFNgammaKO and IFNalpha/betaRKO mice at levels higher than those observed in control mice, implying that baseline levels of these cytokines control HBV replication in the absence of inflammation. We also showed that IFNgamma mediates most of the antiviral effect of the CTLs while IFNalpha/beta is primarily responsible for the early inhibitory effect of LCMV and adenovirus on HBV replication. In addition, we showed that the hepatic induction of IFNalpha/beta observed after injection of poly(I. C) is sufficient to inhibit HBV replication and that a similar antiviral effect is achieved by systemic administration of very high doses of IFNalpha. We also compared the relative sensitivity of LCMV and adenovirus to control by IFNgamma, TNFalpha, or IFNalpha/beta in these animals. Importantly, IFNalpha/betaRKO mice, and to a lesser extent IFNgammaKO mice, showed higher hepatic levels of LCMV RNA and adenovirus DNA and RNA than control mice, underscoring the importance of both interferons in controlling these other viral infections as well.
我们之前已经表明，在注射乙肝病毒特异性细胞毒性T淋巴细胞（CTL）或感染无关的嗜肝病毒（包括淋巴细胞性脉络丛脑膜炎病毒（LCMV）和腺病毒）后，转基因小鼠肝脏中的乙肝病毒（HBV）复制受到非细胞病变性抑制。这些效应由γ干扰素（IFNγ）、肿瘤坏死因子α（TNFα）和IFNα/β介导。在本研究中，我们将HBV转基因小鼠与IFNγ基因缺陷（IFNγKO）、TNFα受体（TNFαRKO）或IFNα/β受体（IFNα/βRKO）基因缺陷的小鼠进行杂交，以确定每种细胞因子对在这些系统中观察到的抗病毒效应的相对贡献。有趣的是，我们发现HBV在未处理的IFNγKO和IFNα/βRKO小鼠中的复制水平高于对照小鼠，这意味着在没有炎症的情况下，这些细胞因子的基线水平控制着HBV复制。我们还表明，IFNγ介导了CTL的大部分抗病毒效应，而IFNα/β主要负责LCMV和腺病毒对HBV复制的早期抑制作用。此外，我们表明注射聚肌苷酸-聚胞苷酸（poly(I:C)）后观察到的肝脏中IFNα/β的诱导足以抑制HBV复制，并且通过全身给予非常高剂量的IFNα也能达到类似的抗病毒效果。我们还比较了LCMV和腺病毒在这些动物中受IFNγ、TNFα或IFNα/β控制的相对敏感性。重要的是，IFNα/βRKO小鼠，以及程度较轻的IFNγKO小鼠，其肝脏中LCMV RNA和腺病毒DNA及RNA的水平高于对照小鼠，这也强调了这两种干扰素在控制这些其他病毒感染中的重要性。
