Relationship between the Replication of Hepatitis B Virus and the Localization of Virus Nucleocapsid Antigen (HBcAg) in Hepatocytes

Abstract

SUMMARYAccording to the localization of hepatitis B virus (HBV) core antigen (HBcAg), detected by the avidin biotin complex method, infected hepatocytes were classified into three types, i.e. those having nuclear (type I), nuclear and cytoplasmic (type II) or only cytoplasmic (type III) antigen. HBcAg-positive hepatocytes of all specimens (three) from non-specific reactive hepatitis and of most (five of seven) from chronic persistent hepatitis (CPH) patients were only type I; the other two CPH samples and all (seven) chronic active hepatitis samples were composed of a mixture of types I, II and III. Linear correlations between the frequency of type I, as well as that of all types (I, II and III) of the HBcAg-positive hepatocytes, and the amount of HBV DNA in serum were found. The relative HBV production of HBcAg-positive hepatocytes (serum HBV DNA amount/frequency of HBcAg-positive cells) was 0.11 in type I and 0-07 in all hepatocytes including types I, II and III. HBV core particles and complete HBV particles were found in type I hepatocytes. On the other hand, these particles were not found in a predominantly type III liver specimen. These results suggest that type I hepatocytes are more involved in the propagation of HBV than types II and III.Several immunological, histological and biochemical studies on the relationship between the expression of hepatitis B virus (HBV)-related antigens, especially of HBV core antigen (HBcAg), and viral replication have been performed using serum and liver tissues from patients with type B hepatitis. The following connections have been found. (i) When hepatitis B e antigen (HBeAg), which is part of HBcAg (Ohori et al., 1979; Mackay et al., 1981), is detectable in serum, Dane particles, HBV-specific DNA polymerase and DNA are demonstrable in the serum (Nordenfelt & Kjellen, 1975;Imai et al., 1976;Ohori et al., 1980) and HBcAg and HBV DNA in liver tissues (Bonino et al., 1981;Hadziyannis et al., 1983). (ii) The localization of HBcAg in hepatocytes varies even in the same tissue (Gudat et al., 1975;Yamada & Nakane, 1977; Huang & Neurath, 1979). However, because conflicting results have been obtained in studies of the localization of HBcAg and the presence of HBV DNA in hepatocytes, valid conclusions about the correlation between HBV replication and HBcAg expression in hepatocytes can not yet be drawn (Blum et al., 1984;Burrell et al., 1985).In the present study, we have examined staining conditions for the detection of HBcAg, and classified the HBcAg-positive hepatocytes with respect to the localization of this antigen in liver tissues from patients whose sera were positive for HBeAg. The amount of HBV DNA in serum was determined and electron microscopic observations were made. These results are discussed with regard to virus replication in the three types of hepatocyte. t Present address:

Expression of hepatitis B virus nuclear core antigen in young cirrhotic patients is associated with an unfavourable long‐term outcome

“…Consistently, by use of polyclonal antibodies, it was observed that HBcAg localized mainly in the nuclei in patients with minor hepatitis activities and the nuclear HBcAg decreased significantly with concomitant increase of cytoplasmic HBcAg expression in patients with active hepatonecroinflammation [7]. Similar observations have been made by several other groups [8][9][10][11][12][13]. Intriguingly, these studies also showed that the presence of nuclear HBcAg was associated with high serum levels of HBV-DNA in spite of low hepatitis activities [2,[8][9][10]13].…”

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

“…In HepaRG cells, which can be infected with HBV, core has been detected in the cytoplasm and occasionally in the nucleus (Gripon et al, 2002). The localization of core in humans is also variable: Akiba et al (1987) and Sharma et al (2002) observed more frequent nuclear localization while others observed a mainly cytoplasmic core and/or capsid localization (Liu et al, 2009;Michalak & Nowosławski, 1982;Park et al, 1999;Petit & Pillot, 1985). In terms of disease and viral load, the majority of studies associate cytoplasmic capsids with high hepatocellular injury (Chu et al, 1995Kim et al, 2006;Naoumov et al, 1990) and a low level viraemia (Liu et al, 2009) while nuclear dominance is associated with high viral load and minor hepatitis activity .…”

Three Distinct Southern Blot Hybridization Patterns of HBV-DNA in the Sera of HBV Carriers.

“…Hence, increased expression of viral antigen on hepatocytes due to high HBV replication leads to marked hepatitis (Chu et al 1985; Hsu et al 1987). On the other hand, we examined previously the form of HBV in hepatocytes by electron microscopy and reported that viral particles, including Dane particle and core particle, were observed in HBV carriers without hepatitis, but not in those with active liver disease (Akiba et al 1987). These facts suggest that the replication state of HBV may differ according to the disease activity.…”