Start or End? ; One of the Biggest Mysteries is Finally Solved?

Abstract

It is now a half century since hepatitis B virus (HBV) was identified by Blumberg et al. [1]. This virus is a small DNA virus whose genome is partially double stranded circular DNA and is only 3.2 kb in size. The viral genes are compactly organized and four genes; core, S, polymerase and X are identified [2].There are about 360 million people infected with the virus worldwide, forming one of the biggest infectious diseases and one of the most serious health programs of human being [3]. HBV infection causes not only severe acute hepatitis including fulminant hepatitis that is highly lethal, but also chronic hepatitis leading liver cirrhosis and hepatocellular carcinoma especially through vertical infection. Treatment against HBV infection consists of interferon therapy and anti-viral drugs. The interferon therapy is, however, very limited and not as effective as that against Hepatitis C Virus (HCV) infection [4]. And furthermore, anti-HBV drugs, all of which are nucleoside analogues, were developed as anti-Human Immunodeficiency Virus (HIV) drugs not as anti-HBV ones and the HBV polymerase specificity and peculiarity were not considered. Needless to say, both viruses have a reverse transcription process of their replication cycles and thus reverse transcriptase activity work in a similar way, i.e., their activity center is composed of an MYDD motif [2]. These kinds of anti-viral drugs always lead to generation and expansion of mutants that escape their effectiveness.As mentioned, exploitation and development of new really effective drugs against HBV considering its viral life cycle and gene functions is one of the most important issues for human health. But we have not had very useful HBV infection system in vitro and in vivo to study detail viral life cycle and its pathogenesis. Hepadnaviruses are highly species specific and tissue specific and HBV never infects present hepatocyte-originated human hepatocellular carcinoma cell lines such as HepG2. [5,6], it is not easy to hatch and raise these kinds of animal and to prepare primary hepatocytes from these animals.As for in vitro infection systems, two systems are available at present; one is Primary Human Hepatocytes (PHH) or tree shrew (Tupaia belangen) [7] which is also susceptible to HBV as human and chimpanzee and another is HepaRG [8], a cultured Human Hepatocellular Carcinoma (HCC) cell line established from HCV caused HCC.These in vitro systems facilitate our knowledge about how HBV infects hepatocytes, but still not good enough because of their commercialism, invariability dependent on the lot and takes cost for preparation and time to induce infectivity.A recent splendid report by Yan et al. may improve such inconvenience to study HBV [8]. For long time, we have been searching for HBV receptors and several molecules including those from the DHBV system were nominated as HBV receptors but they had never contributed establishment for HBV infection systems in vitro, though many data have suggested that the ligand on the HBV side for the receptor must be in...

Successful Generation of Hepatitis B virus (HBV) Pseudotype Particle; A Versatile Tool for Identification of the HBV Receptor and Investigation of HBV Infectivity

“…None of them, however, has been utilized for establishing an in vitro HBV infection system as an HBV receptor molecule. And most recently, NTCP (sodium-taurocholate co-transporting protein) has been nominated as a plausible HBV receptor molecule, which has been under evaluation [45][46][47].…”