It is generally accepted that the host's immune response rather than the virus itself is causing the hepatocellular damage seen in acute and chronic hepatitis B virus (HBV) infections. However, in situations of severe immune suppression, chronic HBV patients may develop a considerable degree of liver disease. To examine whether HBV has direct cytopathic effects in severely immune compromised hosts, we have infected severe combined immune deficient mice (uPA-SCID), harboring human liver cells, with HBV. Serologic analysis of the plasma of HBV-infected animals revealed the presence of extremely high amounts of viral genomes and proteins. Histological analysis of the livers of uPA-SCID chimeras infected with HBV for more than 2 months showed that the majority of human hepatocytes had a ground-glass appearance, stained intensely for viral proteins, and showed signs of considerable damage and cell death. This histopathologic pattern closely resembles the picture observed in the livers of immunosuppressed HBV patients. These lesions were not observed in animals infected with HBV for less than 1 month. Ultrastructural analysis of long-term-infected hepatocytes showed a highly increased presence of cylindrical HBsAg structures, core particles, and Dane particles compared to short-term-infected hepatocytes. These long-term-infected hepatocytes also contained elevated amounts of HBV cccDNA. In conclusion, HBV causes dramatic intracellular changes and hepatocellular damage in the human hepatocytes that reside in a severely immune deficient mouse. These lesions show much resemblance to the ones encountered in immunosuppressed chronic HBV patients. Our observations indicate that HBV may be directly cytopathic in conditions of severe immune suppression.

Summary Identification of gene products exclusively or abundantly expressed in cancer may yield novel tumour markers. We recently isolated a number of cDNA clones, including a-prothymosin, from rat hepatocellular carcinoma (HCC) using a subtraction-enhanced display technique. a-Prothymosin is involved in cell proliferation and is regulated by the oncogene c-myc in vitro. In the present study, we analysed a-prothymosin gene expression and its correlation with c-myc in patients with HCC, cirrhosis and adenoma and in normal controls. Hepatic aprothymosin messenger RNA (mRNA) levels were two-to 9.2-fold higher in tumoral tissues than in adjacent non-tumoral tissues in 14 of 17 patients with HCC, regardless of coexisting cirrhosis and viral hepatitis. No marked difference in a-prothymosin mRNA levels was present in patients with adenoma and hepatic cirrhosis and in healthy controls. The c-myc mRNA amounts were two-to fivefold increased in 11 of 17 patients with HCC and correlated significantly with those of a-prothymosin (P < 0.001). In situ hybridization revealed that increased aprothymosin mRNA was localized in the tumour nodules of the patients with HCC. These data suggest that overexpression of a-prothymosin in HCC patients, correlated with c-myc, is possibly involved in the tumorigenic process and may be a novel molecular marker for human HCC.

Summary Suppressor gene loci involved in the development of hepatocellular carcinoma (HCC) have not been fully identified. The aim of this study was to look for consistent allele loss, or loss of heterozygosity (LOH), in HCC which might represent such gene loci. We have prepared DNA from tumour and non-tumour material from 16 patients with HCC (nine with and seven without liver cirrhosis). Tumour DNA was compared with non-tumour DNA by Southern analysis performed with a panel of 22 probes recognising restriction fragment length polymorphisms assigned to chromosomes 1, 4, 5, 7, 9, 11, 12, 13, 14, 16, 17,

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