Hepatitis B virus PreS/S gene variants: Pathobiology and clinical implications

Abstract

The emergence and takeover of hepatitis B virus (HBV) variants carrying mutation(s) in the preS/S genomic region is a fairly frequent event that may occur spontaneously or may be the consequence of immunoprophylaxis or antiviral treatments. Selection of preS/S mutants may have relevant pathobiological and clinical implications. Both experimental data and studies in humans show that several specific mutations in the preS/S gene may induce an imbalance in the synthesis of the surface proteins and their consequent retention within the endoplasmic reticulum (ER) of the hepatocytes. The accumulation of mutated surface proteins may cause ER stress with the consequent induction of oxidative DNA damage and genomic instability. Viral mutants with antigenically modified surface antigen may be potentially infectious to immune-prophylaxed patients and may account for cases of occult HBV infection. In addition, preS/S variants were reported to be associated with cases of fulminant hepatitis as well as of fibrosing cholestatic hepatitis, and they are associated with cirrhosis and hepatocellular carcinoma development.

Serologic and molecular characteristics of hepatitis B virus infection in vaccinated schizophrenia patients in China

“…The presence of vaccine escape associated amino acid substitutions in the major hydrophilic region (MHR) of the HBV S gene based on previous studies was investigated [14][15][16]. In total, 24 and 103 amino acid substitutions in amplified S gene fragments were observed in the viruses isolated from the schizophrenia and control groups, respectively.…”

Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

“…The ER plays a major role in the synthesis, folding and trafficking of secretory and membrane proteins that correlate with the cellular response known as ER stress. A considerable amount of experimental data have confirmed the potential pro-oncogenic role of preS mutated gene products via accumulation in the ER with enhanced ER stress and ROS [51] . The preS mutated proteins accumulating in the ER can trigger c-Raf-1/Erk2 signaling, which results in AP1 and NFκB activation, enhanced proliferative activity of hepatocytes and an increased incidence of liver tumors in transgenics [52] .…”

“…The HCCassociated HBV variant preS has been identified in the pre-S2 start codon and/or in deletions of the 5'terminal of the preS2 region and preS1 mutation with deletions of the 3'terminal of preS1 [50,51] . These preS region mutant products induce the accumulation of mutated L protein in the endoplasmic reticulum (ER) of hepatocytes.…”

Variations and mutations in the hepatitis B virus genome and their associations with clinical characteristics

“…Because the pre-S2 region includes an epitope targeted by cytotoxic T lymphocytes, type Ⅱ GGHs may represent an immune escape mutant [56] . It has also been reported that pre-S mutants could induce endoplasmic reticulum stress, followed by oxidative DNA damage and genomic instability [57,58] . Recent studies have also shown that the pre-S2 region upregulates human telomerase reverse transcriptase expression and transactivates forkhead box P3 expression, which may promote the development of HCC [59] .…”