the hepatitis B virology and immunology
The hepatitis B virology and immunologyIn order to understand what happens when a person is infected with hepatitis B it is helpful to know more about the virus. This section attempts to convey information about the hepatitis B virus, how it reproduces and the human bodies response to the virus. This one chapter could fill a text book, or more, and so the information is simplified.
3.1 What is the Hepatitis B Virus.
Hepatitis B is a DNA Virus of the hepadnaviridae family of viruses. It replicates within infected liver cells (hepatocytes ). The infectious ("Dane") particle consists of an inner core plus an outer surface coat.
In real life----the virus is a spherical particle with a diameter of 42nm (1nm = 0.000000001 metres) and is composed as follows. There is an outer shell (or envelope) composed of several proteins known collectively as HBs or surface proteins (indicated by 's' in Fig 2.). This outer shell is frequently referred to as the surface coat. The outer surface coat surrounds an inner protein shell, composed of HBc protein (shown as 'c' in Fig 2). This inner shell is referred to as the core particle or capsid. Finally the core particle surrounds the viral DNA ('D') and an enzyme DNA Polymerase ('p').
3.2 How does the virus replicate.
When the virus enters the body of a new host it's initial response, if it's gets past the immune system, is to infect a liver cell. To do this the virus attaches to a liver cells membrane and the core particle enters the liver cell. The core particle then releases it's contents of DNA and DNA polymerase into the liver cell nucleus.
From within the cell nucleus the hepatitis B DNA causes the liver cell to produce, via messenger RNA; surface (HBs) proteins, the core (HBc) protein, DNA polymerase, the HBe protein, HBx protein and possibly other as yet undetected proteins and enzymes.
DNA polymerase causes the liver cell to make copies of hepatitis B DNA. I.e. it is believed that the replication of HBV DNA it does not go via RNA(?). Via the above process, versions of the hepatitis B virus are constructed by the liver cell . These copies of the virus and are released from the liver cell membrane into the blood stream and from there can infect other liver cells and thus replicate effectively. However when reproducing, mistakes may be made in copying viral DNA and this results in different strains and mutant strains of hepatitis B occurring.
The incubation of the Hepatitis B Virus (hepatitis B) is about 6 to 25 weeks (i.e. before physical and generally detectable histological or physical symptoms occur) however there are several biochemical and histological changes that occur in stages after infection with the hepatitis B virus.
3.3 Hepatitis B Antigens and Markers.
The various components produced by hepatitis B, while reproducing, are detailed below. Some of these components enter the blood stream and cause detectable changes, some may only be determined via liver biopsy and others require sophisticated, experimental or unreliable tests.
i) Hepatitis B DNA (HBV DNA)
This is one of the first things that can be detected in the bloodstream after initial infection. It can be detected as soon as 1 week after infection using sensitive tests. It is believed that the level of HBV DNA may indicate how fast the virus is replicating(?). The test for HBV DNA is however expensive and difficult to perform, it is therefore not frequently used. Tests for HBV DNA are not performed as a standard test and generally only used as indicators of disease progression, suitability for therapy and research purposes.
ii) Hepatitis B DNA polymerase. (HBV DNA Polymerase, DNAp)
This enzyme can be detected in the bloodstream soon after initial infection by hepatitis B at about the same time as HBV DNA. I.e. generally within a 1 week or so after infection. Tests for HBV DNA polymerase are not performed as a standard test and generally only used as indicators of disease progression, suitability for therapy and research purposes.
iii) Hepatitis B Core protein. (HBcAg)
The core protein (HBc) is not detectable in the bloodstream, however it can be detected in the sample of liver cells taken after a liver biopsy. Generally the HBc proteins link together to form the hepatitis B core that encapsulate HBV DNA and DNA Polymerase.
iv) Hepatitis B Surface protein(s). (HBsAg)
The outer surface coat composed of hepatitis B surface proteins is produced in larger quantities than required for the virus to reproduce. The excess surface proteins clump together into spherical particles of between 17-25nm in diameter but also form rods of variable length. In some cases these particles encapsulate a core particle and produce a complete, and infectious, virus particle that enters the blood stream and can infect other liver cells. The excess spheres, rods and also complete viral particles enter the blood stream in large numbers and are easily detectable. It does however take a while for these proteins to appear.
The incubation of the Hepatitis B Virus (hepatitis B) is between 6 to 25 weeks. After infection and 1 to 6 weeks before symptoms occur HBsAg appears. A positive test for the presence of hepatitis B surface protein (HBsAg), is the standard currently taken to indicate current infection with hepatitis B. If HBsAg is present for more than 6 months this is generally taken to indicate chronic infection.
It is thought that excess HBs proteins produced may allow infectious viral particles to escape the immune system by mopping up any low levels of surface antibodies that may be produced by the immune system.
v) HBe Protein. (HBeAg or 'e' antigen)
The Hepatitis 'e' antigen (HBeAg) is a peptide and normally detectable in the bloodstream when the hepatitis B virus is actively reproducing, this in turn leads to the person being much more infectious and at a greater risk of progression to liver disease. The exact function of this non structural protein is unknown, however it is thought that HBe may be influential in suppressing the immune systems response to HBV infection(?). HBeAg is generally detectable at the same time as HBsAg and disappears before HBsAg disappears. The presence of HBeAg in chronic infection is generally taken to indicate that HBV is actively reproducing and there is a higher probability of liver damage. In acute infection HBeAg is generally only transiently present.
However mutant strains of HBV exist that replicate without producing HBeAg. In many cases infection with these mutant strains is more aggressive than HBe producing strains.
vi) HBx Protein.
The function of this protein is not yet known. Although it can be detected current tests are unreliable as other proteins interfere with the results.
3.4 How the Human Body Responds to Infection.
This section details how the human body responds to an initial infection with hepatitis B. In people with immune suppression, undeveloped immune systems (I.e. infants and children), certain genetic traits or other as yet unknown factors these may not occur.
Round 90% of infected people will recover from Hepatitis B and around half of these will have had no symptoms. Recovery means that no HBsAg is found in the blood and the Hepatitis B Antibody (HBsAb) is present. HBsAb usually persists for life after recovery.
i) Antibodies to HBc (HBcAb).
The first detectable antibody to appear around 8 weeks after infection with HBV are antibodies to the HBV core protein. These antibodies to HBcAg (HBcAb) do not neutralise the virus. HBcAb's persist in serum after an infection with HBV has been defeated and testing for this antibody has been used to detect previous exposure to the live virus.
ii) ALT alanine aminotransferase and AST (aspartate aminotransferase).
ALT and AST are enzymes produced in liver cells that can be detected in the blood stream. The normal range for ALT is between 0-40. When liver cells are damaged these enzymes are released and elevated levels are detected in serum. The value of ALT in the blood stream is generally taken to be an indicator of the damage that hepatitis causing to liver cells. However damage may be occurring with little or no elevation of ALT (this is especially true for hepatitis C and people with end stage liver disease).
ALT and AST and other substances are measured when a liver function test is taken. However other drugs and especially alcohol can elevate these readings artificially. It is therefore important to avoid these things before a liver function test and/or inform your doctor of any drugs you may be taking or have taken in weeks previous to the test. You may find it useful to keep a record of your ALT to track disease progression and the effects any treatments) you are taking is having.
After an initial infection and at around the same time as HBcAb appears in the blood stream the level of ALT starts to rise sharply. The rise in ALT is due to damage to the liver cells, one theory is that the damage to liver cells is not caused directly by the virus, i.e. the virus does not kill liver cells, but by the human bodies own immune system killing infected and surrounding cells. In patients with compromised immune systems and/or with HIV infection there is increased risk of the infection becoming chronic but damage done by the chronic infection appears mild in comparison to people not infected with HIV. In cases of acute infection ALT starts to drop at around the same time as when the 'e' antigen is no longer detectable and is down to normal when antibodies to the surface antigen appear.
iii) Interferon.
When a human cell is exposed to a new virus it usually produces a group of substances known as interferons. It is believed that interferons modulate (alter) the immune system, alter cell membranes to reduce infection of surrounding uninfected cells and also causes many changes. This naturally produced interferon assists the body in fighting hepatitis B. However it was discovered that the interferon response was deficient in some people and also infants/ children with immature immune systems. This finding lead to interferon being considered as a treatment.
iv) Antibodies to HBe protein (HBeAb)
Antibodies to the 'e' antigen (HBeAb) normally appears a few weeks after HBeAg is no longer detectable. The presence of HBeAb is generally taken to be a good sign and indicates a favourable prognosis.
v) Antibodies to HBs protein (HBsAb)
These are generally the last antibodies to appear. HBsAb can neutralise the hepatitis B virus and there appearance taken as an indicator that an initial infection has been defeated.
HBsAb can also be induced to appear by vaccination and so provide protection against hepatitis B. However the immune response produced by vaccination may not be 100%. Although very rare, hepatitis B infection has occurred in vaccinated individuals. It is believed that this may be due to mutant virus strains that express different surface proteins to those used in the genetically engineered vaccine
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