What is HBV?
The Hepatitis B Virus
The Hepatitis B virus (HBV) is a mostly double-stranded DNA virus in the Hepadnaviridae family. One of five hepatitis viruses, HBV causes acute and chronic hepatitis in humans. Despite the current availability of an effective vaccine, almost 1.2 million people worldwide still die each year from HBV related diseases (CDC). An acute HBV infection usually causes only mild symptoms and the majority of infected adults successfully clear the virus and acquire life-long immunity. In acute hepatitis, it takes about 1 to 6 months from the time of infection for the disease to manifest itself. Early symptoms include nausea and vomiting, loss of appetite, fatigue, and muscle and joint aches. Jaundice, together with dark urine and light stools, follows. Only about 1 percent of patients infected with hepatitis B die due to liver damage in this early stage (Poynard, 2002). The risk of becoming chronically infected depends on the age at the time of infection. More than 90 percent of newborns, 50 percent of children, 5 percent of adults infected with HBV develop chronic hepatitis. Those who are unable to produce an effective immune response allow the virus to replicate for long periods in their livers, causing chronic hepatitis HBV infection, cirrhosis of the liver, and hepatocellular carcinoma (HCC) (Yen, 2002). Transmission of the hepatitis B virus is through contact with blood and other bodily fluid. Chronic hepatitis B is treated with a manufactured form of interferon, a protein made naturally by the body to boost the immune system and to regulate other cell functions (CDC). A vaccine is available to prevent HBV which originally consisted of purified HBV surface antigens (HBsAg) prepared from the serum of carriers and wash chemically treated to kill any contaminating viruses, but the current vaccine is genetically engineered HBsAg produced in yeasts (Yen, 2002).
Genome: The HBV virion genome is circular and approximately 3.2 kb in size and consists of DNA that is mostly double stranded. It has compact organization, with four overlapping reading frames running in one direction and no noncoding regions. The minus strand is unit length and has a protein covalently attached to the 5' end. The other strand, the plus strand, is variable in length, but has less than unit length, and has an RNA oligonulceotide at its 5' end. Thus neither DNA strand is closed and circularity is maintained by cohesive ends (Strauss, 2002). The four overlapping open reading frames (ORFs) in the genome are responsible for the transcription and expression of seven different hepatitis B proteins. The transcription and translation of these proteins is through the used of multiple in-frame start codons. The HBV genome also contains parts that regulate transcription, determine the site of polyadenylation and a specific transcript for encapsidation into the nucleocapsid. The genomic arrangement of the hepatitis B virus family makes it unique among viruses. The unusually packaged may indicate that the method of replication employed by HBV is not of conserved DNA replication (Garces, HBVP).
Life Cycle: In order to reproduce, the hepatitis
B virus, must first attach onto a cell which is capable of supporting its
replication. Although hepatocytes are known to be the most effective cell
type for replicating HBV, other types of cells in the human body have be
found to be able to support replication to a lesser degree. The initial
steps following HBV entry are not clearly defined although it is known
that the virion initially attaches to a susceptible hepatocyte through
recognition of cell surface receptor that has yet to be indified (Garces,
HBVP). The DNA is then enters into the nucleus, where it is known to
form a convalently closed circular form called CCC
DNA. The (-) strand of such CCC DNA
is the template for transcription by cellular RNA polymerase II of a longer-than-genome-length
RNA called the pregenome and shorter, subgenomic transcripts, all of which
serve as mRNAs. The shorter viral mRNAs are translated by ribosomes attached
to the cell's endoplasmic reticulum and the proteins that are destined
to become HBV surface antigens in the viral envelope are assembled. The
pregenome RNA is translated to produce a polymerase protein, P, which then
binds to a specific site at the 3' end of its own transcript, where viral
DNA synthesis eventually occurs. Occuring at the same time as capsid formation,
the RNA-P protein complex is packaged and reverse transcription begins.
At early times after the infection, the DNA is recirculated to the nucleus,
where the process is repeated, resulting in the the accumulation of 10
to 30 molecules of CCC DNA and an increase in viral mRNA concentrations
(Flint et al.,
HBV Life Cycle
HBV Particle Types: The hepatitis B virion,
also known as the Dane particle, is the one infectious particle found within
the body of an infected patient. This virion has a diameter of 42nm and
its outer envelope contains a high quantity of hepatitis b surface proteins.
The envelope surrounds the inner nucleocapsid which is made up of 180 hepatitis
B core proteins arranged in an icosahedral arrangement. The nucleocapsid
also contains at least one hepatitis b ploymerase protein (P) along with
the HBV genome.
In infected people, virions actually compose a small minority of HBV-derived particles. Large numbers of smaller subviral particles are also present, that uusually outnumber the virions by a ratio of 100:1. These two other subviral particles, the hepatitis B filament and the hepatitis B sphere, are often referred to as a group named surface antigen (HBsAg) particles. They are both 22nm in diameter and are totally composed of hepatitis B surface proteins. The sphere contains both middle and small hepatitis surface proteins whereas the filament also includes large hepatitis B surface protein. The absence of the hepatitis B core, polymerase, and genome causes these particles to have a non-infectious nature. High levels of these non-infectious particles can be found during the acute phase of the infection. Since the non-infectious particles present the same sites as the virion, they induce a significant immune response and are thought to be non-advantagous for the virus. However, it is also believed that the presence of high levels of non-infectious particles may allow the infectious viral particles to travel undetected by antibodies through the blood stream (Garces, HBVP).
Hepatitis B Antigens: There are three different types of hepatitis b antigens encoded by the HBV genome.