Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice.

Chisari, Francis V.; Filippi, P; Buras, Jon A.; McLachlan, Alan; Pópper, Hans; Pinkert, Carl A.; Palmiter, Richard D.; Brinster, Ralph L.

doi:10.1073/pnas.84.19.6909

Cited by 324 publications

(286 citation statements)

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“…14,15 The pathogenetic association of viral load and cell death has been documented in HepG2 lines and transgenic mice models. 16,17 Recently, the detection of the precore mutant 5,6,9,18 and mutational changes in the S and pre-S genome 19,20 in a few patients raised the possibility of the pathogenetic significance of viral mutations.…”

Section: Discussionmentioning

confidence: 99%

Fibrosing cholestatic hepatitis in renal transplant recipients with hepatitis C virus infection

et al. 1999

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Fibrosing cholestatic hepatitis (FCH) has been described as a specific manifestation of hepatitis B virus (HBV) infection in liver allograft recipients characterized by a rapid progression to liver failure. Only sporadic cases have been reported in other immunocompromised groups infected with HBV and in a few transplant recipients with hepatitis C virus (HCV) infection. We present the occurrence of FCH in 4 HCV-infected renal transplant recipients within a series of 73 renal transplant recipients with HCV infection followed up closely serologically and with consecutive liver biopsies. All 4 patients received the triple-immunosuppressive regimen (azathioprine, cyclosporine A, methylprednisolone). The interval from transplantation to the appearance of liver dysfunction was 1 to 4 months and to histological diagnosis, 3 to 11 months. The biochemical profile was analogous to a progressive cholestatic syndrome in 3 patients, whereas the fourth patient had only slightly increased alanine aminotransferase and ␥-glutamyl transferase (␥GT) levels. Liver histological examination showed the characteristic pattern of FCH in 2 patients, whereas the other 2 patients had changes compatible with an early stage. All patients were anti-HCV negative at the time of transplantation, whereas 2 patients, 1 with incomplete and 1with complete histological FCH features, seroconverted after 3 and 31 months, respectively. The patients were HCV RNA positive at the time of the first liver biopsy and showed high serum HCV RNA levels (14 to 58 ؋ 10 6 Eq/mL, branched DNA). HCV genotype was 1b in 3 patients and 3a in 1 patient. After histological diagnosis, immunosuppression was drastically reduced. Two patients died of sepsis and liver failure 16 and 18 months posttransplantation, whereas the seroconverted patients showed marked improvement of their liver disease, which was histologically verified in 1 patient. In conclusion, FCH can occur in HCV-infected renal transplant recipients. It seems to develop as a complication of a recent HCV infection during the period of maximal immunosuppression and is associated with high HCV viremia levels. There are indications that drastic reduction of immunosuppression may have a beneficial effect on the outcome of the disease.

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Section: Discussionmentioning

confidence: 99%

Fibrosing cholestatic hepatitis in renal transplant recipients with hepatitis C virus infection

et al. 1999

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“…46 Different from the findings with MHBs DNA, co-immunizations of LHBs encoding DNA with either pcD/3-IL2 or pRJB-GM had no augmenting effect on cellular and humoral immune responses to HBV envelope proteins. LHBs cannot be secreted by itself in hepatoma and other cell lines, including myoblast cells, even though it is targeted co-translationally to the rough endoplasmic reticulum 34,47,48 and inhibits the secretion of MHBs and SHBs by forming heteromultimers when produced in large amounts. A recent study demonstrated that LHBs itself can form 20-nm particles which are retained in a post-rough endoplasmic reticulum compartment, possibly by interacting with calnexin and other regulatory endoplasmic reticulum proteins.…”

Section: Discussionmentioning

confidence: 99%

Cytokine and hepatitis B virus DNA Co-immunizations enhance cellular and humoral immune responses to the middle but not to the large hepatitis B virus surface antigen in mice

et al. 1998

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Genetic immunization is a potentially useful strategy to prevent or treat hepatitis B virus (HBV) infection. We have previously shown that HBV envelope proteins are highly immunogenic using this technique. The large envelope protein (LHBs), however, induced significantly weaker humoral and cellular immune responses when compared with the middle envelope protein (MHBs). We studied the effect of co-immunizations with cytokine DNA expression constructs encoding for interleukin (IL)-2 and (GM-CSF) on the immunogenicity of LHBs at the B-and T-cell level. Co-immunizations of mice with plasmids encoding for MHBs and IL-2 or GM-CSF increased anti-HBs responses, helper T-cell proliferative activity, and cytotoxic T lymphocyte (CTL) killing. In contrast, co-immunizations of plasmids encoding for LHBs and IL-2 or GM-CSF had no effect on humoral and cellular immune responses. LHBs did not inhibit the production or secretion of IL-2 and GM-CSF. In addition, IL-2, tumor necrosis factor alfa (TNF-␣), and interferon gamma (IFN-␥) had no suppressive effect on HBV envelope protein expression in vitro. Based on these data, MHBs, but not LHBs, genetic immunization can be augmented by IL-2 or GM-CSF cytokines. (HEPATOLOGY 1998;28:202-210.)Hepatitis B virus (HBV) is a noncytopathic, hepatotropic virus infecting more than 350 million individuals worldwide. 1 Hepatitis B is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. 2 The cellular immune response to HBV is thought to be responsible for viral clearance and pathogenesis of liver disease. In acutely infected patients who successfully clear the virus the CD4ϩ and CD8ϩ T-cell response to HBV is vigorous, polyclonal, and multispecific. [3][4][5][6][7][8][9][10] The T cells typically secrete type-1 antiviral cytokines, such as interferon gamma (IFN-␥) and tumor necrosis factor alfa (TNF-␣), upon antigen stimulation. By contrast, in chronically infected patients, the T-cell response is relatively weak and is antigenetically more restricted, except during acute exacerbations of chronic disease or after spontaneous or IFN-␣ induced viral clearance. [11][12][13] The cytokine profile of the intrahepatic HBVspecific T cells is variable in chronically infected individuals. The observation of spontaneous HBV clearance in some chronically infected individuals implies that the suboptimal cellular immune response may be reversible; therefore, strategies designed to boost the HBV-specific T-cell immune response, to alter the balance between the cytopathic and the regulatory components of the response, or to mimic the regulatory functions of the T-cell response in the liver may be able to terminate persistent infection.In this regard, genetic immunization offers the potential advantage of inducing cellular and humoral immune responses against conserved viral epitopes because this approach uses DNA expression plasmids, instead of proteins, for vaccination. This technique involves the transfer of a viral gene into muscle cells and antigen presenting cells by a plasmid vec...

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“…21 Electron microscopy studies of liver sections performed from the mice overexpressing the L protein showed subviral envelope filaments of approximately 20 nm in diameter and very extensive length (up to 800 nm) that accumulate in the ER. 20 The L-protein retention has been also associated with a peculiar syndrome called fibrosing cholestatic hepatitis (FCH), characterized by marked hepatocellular ballooning and prominent cholestasis but minimal inflammation, that occurs in immunosuppressed HBV carriers. 22,23 The same accumulation of HBV subviral envelope filaments in intracellular compartments has been observed by electron microscopy in liver samples of patients suffering from FCH.…”

Section: Discussionmentioning

confidence: 99%

“…This intracellular accumulation is seen in patients in late phases of chronic HBV infection, especially at the phase of cirrhosis, when a high level of intracellular expression of HBV surface proteins is associated with a low level of serum HBV surface proteins. 18,19 Hepatocytes of transgenic mice bearing such L-protein retention accumulation develop characteristic cytopathic effects 20 that can induce a liver regeneration leading to the development of a liver cancer in this model. 21 Electron microscopy studies of liver sections performed from the mice overexpressing the L protein showed subviral envelope filaments of approximately 20 nm in diameter and very extensive length (up to 800 nm) that accumulate in the ER.…”

Section: Discussionmentioning

confidence: 99%

Ultrastructural analysis of hepatitis B virus in HepG2-transfected cells with special emphasis on subviral filament morphogenesis

Roingeard

Sureau

1998

Hepatology

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The intracellular accumulation of empty hepatitis B virus (HBV) particles of filamentous shape leads to a direct cytopathic effect in so-called ground-glass hepatocytes. The aim of this study was to investigate how these filaments can be structurally formed at the cellular level. By electron microscopy, we reexamined the HBV-producer HepG2T-14 cells, which have been described as producing a substantial amount of empty HBV filaments compared with the other forms of HBV particles. Examination of ultrathin sections of HepG2T14 cells revealed the presence of HBV virions and filaments at the periphery of extremely large intracellular cisternae, probably related to a pre-Golgi compartment. Very long filaments appeared to be formed by a tubular budding of a long portion of the cisterna membrane. This phenomenon may be identical to that observed in the hepatocytes of HBV chronic carriers, in which the inability of the infected cell to export long HBV filamentous particles through the cellular secretion pathway seems to be at the origin of a direct cytopathic effect. (HEPATOLOGY 1998;28: 1128-1133.)Hepatitis B virus (HBV) is an enveloped hepatotropic DNA virus that infects a large number of people worldwide. 1 Its genome is encapsulated with a virus-encoded polymerase in a nucleocapsid surrounded by a host-derived lipid envelope bearing three viral surface proteins. 2 The large (L) protein, containing the preS1, preS2, and S domains, is translated from the first start codon of the surface open reading frame. The middle (M) protein, containing the preS2 and S domain, and the small (S) protein are translated from in-frame start codons further downstream. 2 During synthesis, all three proteins are cotranslationally inserted into the endoplasmic reticulum (ER) as transmembrane proteins that can form disulfide bridges with each other. 3 The S protein traverses the ER membrane at least twice to form a cytosolic loop and a luminal domain. 4 The M protein has a similar topology with the additional N-terminal preS2 domain located in the ER lumen. 5 The L protein can adopt two different transmembrane topologies, allowing the exposure of the N-terminal preS domain at either the luminal or the cytosolic side of the ER membrane. 6 This latter form is essential during HBV morphogenesis to establish a protein-protein interaction between the cytoplasmic core particle and a specific sequence within the preS domain of the L protein. 7,8 One peculiarity of HBV morphogenesis compared with that of other viruses is that the surface proteins not only envelop the nucleocapsid to form a mature virion, they are capable of forming subviral empty spherical or filamentous particles in the absence of nucleocapsid. 2 Although the envelopes of all types of HBV particles contain the M and S proteins, filamentous and virion envelopes are richer in the L protein. 2 It is thought that during morphogenesis, the M and S proteins, in the absence of any other viral proteins, can bud into a post-ER/pre-Golgi compartment to form 20-nm spherical particles that ca...

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Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice.

Abstract: Overproduction of the hepatitis B virus (HBV) large envelope polypeptide by transgenic mice containing the entire HBV envelope coding region leads to the formation of extremely long (up to 800 nm), occasionally branching, filamen-

Cited by 324 publications

References 14 publications

Fibrosing cholestatic hepatitis in renal transplant recipients with hepatitis C virus infection

Fibrosing cholestatic hepatitis in renal transplant recipients with hepatitis C virus infection

Cytokine and hepatitis B virus DNA Co-immunizations enhance cellular and humoral immune responses to the middle but not to the large hepatitis B virus surface antigen in mice

Ultrastructural analysis of hepatitis B virus in HepG2-transfected cells with special emphasis on subviral filament morphogenesis

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