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During the assembly of the nucleocapsid of the hepatitis B virus a protein kinase, probably of cellular origin, is encapsidated. This enzyme phosphorylates serine residue(s) localized within the lumen of the particle. By using purified, liver-derived core particles, we characterized the protein kinase activity in the presence of different ions and inhibitors. Controls were performed with cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) and recombinant core particles. We showed that the endogenous protein kinase of the core particles was not inhibited by H89, a specific inhibitor of PKA. Staurosporine, a selective inhibitor of PKC inhibited the endogenous kinase activity only within the first minutes of the reaction. In contrast, quercetine, a selective inhibitor of the protein kinase M (PKM) did not inhibit during the first minutes but inhibited efficiently during later phases of incubation. PKM represents an enzymatically active proteolytic fragment of PKC. These results suggest that PKC is encapsidated into human core particles and is converted to PKM during the in vitro reaction. This conclusion implies the association of a protease activity localized with the HBV nucleocapsid inside liver-derived core particles.

For two reasons hepatitis B virus infection is an important problem in patients with cancer. First, multidrug cancer chemotherapy may reactivate or worsen a previously benign chronic HBV infection. Second, patients undergoing cancer chemotherapy are at an increased risk of acquiring and spreading HBV which may result in an endemic infection. HBV reactivation may precipitate into a severe acute disease including fulminant hepatitis. In contrast, the acquisition of HBV during cancer chemotherapy commonly takes a mild clinical course but frequently leads to persistently high viremia. This state of immunotolerance to viral antigens allows viral replication without any sign of liver cell destruction. Withdrawal of chemotherapy does not cause significant changes if infection occurred during cytotoxic chemotherapy. Infection with HBV during cancer chemotherapy, therefore, may be considered as a model of an induced antigen-specific immunotolerance. In agreement with this hypothesis, vaccination against HBV during cancer chemotherapy does not prevent spread of HBV in oncology wards as it does not produce significant anti-HBs titers. Furthermore, vaccination even suppresses the immune response to later booster doses after chemotherapy has been withdrawn.

I. Replication of hepatitis viruses.- In vitro culture systems for hepatitis B and delta viruses.- Chronic infection in wood-chucks infected by a cloned hepatitis delta virus.- Detection of replicative intermediates of viral RNA in peripheral blood mononuclear cells from chronic hepatitis C virus carriers.- Susceptibility of human liver cell cultures to hepatitis C virus infection.- II. Molecular biology of hepatitis B virus.- Molecular basis of the diversity of hepatitis B virus core-gene products.- Characterization of the endogenous protein kinase activity of the hepatitis B virus.- The hepatitis B virus X gene product transactivates the HIV-LTR in vivo.- Accumulation of a cellular protein bearing c-myc-like antigenicity in hepatic and non-hepatic delta antigen expressing cells.- Duck hepatitis B virus infection, aflatoxin B1 and liver cancer in ducks.- III. Pathogenic and protective immune responses against hepatitis viruses.- Cell mediated immune response to hepatitis B virus nucleocapsid antigen.- Clinical and immunological aspects of hepatitis B virus infection in children receiving multidrug cancer chemotherapy.- Hepatitis C virus infection in type II essential mixed cryoglobulinemias.- Detection of hepatitis B virus DNA by polymerase chain reaction in vaccinated and non-vaccinated Senegalese children.- Duck hepatitis B virus (DHBV) as a model for understanding hepadnavirus neutralization.- IV. Variability of hepatitis B virus.- Implication of genetic variation on the pathogenesis of hepatitis B virus infection.- Hepatitis B virus C-gene variants.- Long-term response to interferon therapy in chronic hepatitis B: importance of hepatitis B virus heterogeneity.- Significance and relevance of serum preS1 antigen detection in wild-type and variant hepatitis B virus (HBV) infections.- Complete nucleotide sequences of six hepatitis B viral genomes encoding the surface antigen subtypes ayw4, adw4q?, and adrq? and their phylogenetic classification.- V. Diagnosis of chronic viral hepatitis.- Role of IgM antibody to hepatitis B core antigen in the diagnosis of hepatitis B exacerbations.- Serum IgM antibodies to hepatitis C virus in acute and chronic hepatitis C.- Isolate antibody to hepatitis C virus core antigen (C22) by RIB A 2: correlation with HCV-RNA and anti-NS5.- Is HCV transmitted by the vertical/perinatal route?.- VI. Clinical course and therapy of chronic viral hepatitis.- Multiple viral infections in HIV-infected children with chronically-evolving hepatitis.- Lymphoblastoid interferon in chronic hepatitis C patients that were "non responders" to recombinant interferon alpha (rIFN alpha).- Non responders to interferon therapy among chronic hepatitis patients infected with hepatitis C virus.- The relationship between LeY antigen and the therapeutic efficacy of interferon in chronic hepatitis C.- Antibodies to interferon alpha in patients.- VII. Liver transplantation and chronic viral hepatitis.- Patterns and mechanisms of hepatitis B/hepatitis D reinfection after liver transplantation.- Hepatitis C virus infection in liver allograft recipients.

HBV surface proteins play a number of functional roles in cellular infection, viral synthesis and in immune responses of the host. Three coterminal proteins of differing sizes and three subdomains of the individual molecules can be recognized. In this brief review, functions of the various proteins and domains are described and their significance as potential immunogens is discussed. Although it is apparent that the surface proteins are involved in the development of persistent HBV infections, the underlying mechanisms of their involvement remain unknown.

We have prepared and used monoclonal antibodies against various populations of full-length and truncated hepatitis B core proteins in order to distinguish between epitopes of HBcAg and HBeAg. Our results show that various epitopes are specific for the different proteins. Certain epitopes, however, are ubiquitous to HBc/e proteins and these are probably exposed on the surface of HBc particles.

Using enzyme immune assay and immune electron microscopy, we have examined the sera of immune-suppressed anti-HBc negative HBV-infected patients for the presence of HBcAg. Our results suggest that free HBV core particles are absent or present only in minute amounts in the blood of chronic carriers and that at the most, only minimal amounts of core antigen are found on the surface of the virus particles.

Using PCR we have studied mononuclear peripheral blood leucocytes (PMBLs) from HBV-infected immunosuppressed patients in order to detect the presence of HBV genomes. Our results indicate that non-transient PMBL infection is common in immunotolerant carriers. In addition, the presence of pregenomic mRNA sequences suggests that virus replication may take place in PMBLs, possibly implicating the latter as a source of virus after replication has ceased in the liver.

A linear relationship between plasma DOPEG (ordinate) and plasma noradrenaline (NA; abscissa) was found during orthostasis as well as during NA infusion. The slope of the former (slopeR) was 13 times steeper than that of the latter (slopI). This difference in slopes suggests that the NA concentration in the synaptic cleft is markedly higher than in plasma. The factor (F) characterizing this concentration difference was obtained from F2 = slopeR/slopeI. It amounted to 3.6.

In the anaesthetized rabbit, plasma DOPEG was used as a tool to estimate both, the total-body rate of neuronal re-uptake of noradrenaline (NA) and the factor F by which the NA concentration in the synaptic cleft exceeds that in plasma. The NA re-uptake rate was 3.5 times higher than the rate of NA net release into plasma and amounted to 863 pmol kg-1 min-1 F was 3.4.