Prevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infection

Abstract

Several types of naturally occurring pre-S mutants in sera or liver tissues in patients with chronic hepatitis B virus (HBV) infection have been identified. To clarify the prevalence and significance of emergence of pre-S mutants, 140 sera and 18 resected livers from patients with HBV were studied. Replicative status was designated as high, intermediate, and low based on the HBV-DNA levels in serum or the expression of HBV antigens in liver. In vitro transfection and Western blot analysis were performed to characterize expression and secretion of HBsAg by the mutant constructs. Five major types (I to V) of pre-S deletion mutants in serum and liver and 2 types (VI and VII) in liver were identified. Pre-S mutant was 6.4% at high replicative phase, 13% at intermediate, and 37.5% at low or nonreplicative phases in serum. In livers, the same tendency existed: pre-S2 deletion mutants emerged and prevailed at a low replicative phase in hepato- Hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic liver diseases. The majority of acute HBV infection are usually self-limited, whereas patients with chronic HBV infection usually pursue a life-long course that can be categorized into 3 phases based on the replicative status of HBV in serum and liver. [1][2][3][4][5][6][7][8][9] In the early or high replicative phase, there are high levels of hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), and HBV DNA in serum and an active replication of HBV genome with nuclear expression of core antigen (HBcAg) in liver. 3,[8][9][10] The HBsAg-expressing hepatocytes or ground glass hepatocytes (GGH) are usually singly scattered in distribution. In the intermediate or immune clearance phase, there is an HLA-restricted cytotoxic T lymphocyte (CTL) response to viral antigen-expressing hepatocytes, which may result in a decrease of HBeAg and HBV DNA in serum. In the late or nonreplicative phase, there is a low titer or absence of viremia and an integration of HBV genomes in host cells. The serum HBsAg, albeit decreased in level, usually persists for life. Contrary to that at the active replicative stage, the HBsAg-containing hepatocytes are inversely increased and clustered in groups at the late or nonreplicative stage, usually associated with an absence of intrahepatic HBcAg expression. [9][10][11] The underlying mechanism of the life-long persistence of serum HBsAg and the novel discrepancy between the levels of HBsAg in serum and liver have not yet been clarified. In the past years, many studies have documented the accumulation of pre-S1 or large surface antigen in the hepatocytes during chronic HBV infection. [12][13][14][15] The large (pre-S1), middle (pre-S2), and small (major) surface proteins have been found to be differentially expressed in hepatocytes at different stages of HBV replication. 13,14 Most liver samples from viremic carriers show a prevalence of 2 smaller surface proteins whereas the large surface antigen is the predominant intrahepatic protein in nonviremic carriers. 14 ...

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

“…Only a few studies have addressed the questions of the rate of HBV mutations in tumor tissues (Pontisso et al, 1984;Raimondo et al, 1988;Clementi et al, 1993). However, our group and others have shown that mutations in basal core promoter, PreC/C, envelope and X sequences can be identified in HCC tissues (Minami et al, 1996;Fan et al, 2000Fan et al, , 2001Tu et al, 2001;Oon et al, 2002;Iavarone et al, 2003;Kao et al, 2003;Kuang et al, 2004). We have observed that in the Core gene, most of the non-synonymous mutations (i.e.…”

Role of viral factors in the natural course and therapy of chronic hepatitis B

“…The deletion over pre-S gene may affect the expression of middle and small surface proteins, resulting in intracellular accumulation of large surface protein [86], and contribute to more progressive liver cell damage and finally hepatocarcinogenesis [87,88]. In our recent case-control study, pre-S deletion mutant of HBV were determined in 202 asymptomatic carriers and 64 HCC patients with chronic HBV genotype B or C infection.…”

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

“…In hepatitis B virus-associated hepatocarcinoma, deletions in the Pre-S1 or Pre-S2 region of hepatitis B virus large surface proteins have been detected (49). These hepatitis B virus mutant large surface proteins were …”

“…Therefore, it is important to investigate whether the mutant large surface protein can induce the expression of COX-2. The expressions of COX-2 and GRP78 were examined in the following cell lines: ML-1 cells, ML-1 transfectants expressing two types of Pre-S mutant surface proteins (49), and an ML-1 control transfectant. The expression of COX-2 was elevated in ML-1 cells expressing hepatitis mutant surface proteins but not in control transfectants (Fig.…”