HBV
Morphology
The Shell is conformed by protein c which creates dimers of protein c. Then, the dimers unites into oligomers and can create 90 icosaedral capsomers (t=3) or 120 icosaedral capsomers (t=4).
The protein c is like an upside down “T” in wich the horizontal bar mediates the dimer conformation and the vertical bar forms a spike protruding outside the virion. This spike has an epitope HBcAg.
Envelope proteins
The three proteins S,M and L are transcripted by the same region because an ORF in one area call E. Depending on which codon of the three do use the cell. The protein S are synthesized in ER (E. reticulum) as a transmembrane protein with two segments and with the loop segment in the lumen of the ER N- glycosilated, this brings the HBsAg epitope, which is very immunogenic and is usually used in vaccination. With protein M occurs similar but Protein L can folde in two ways: one with the loop (containing Pre-S1) outside of the virion or another with the same inside. This last fact is functionally unknown.
During HBV nucleocapsid formation, the RNA pregenome is packaged into the particle’s lumen and first converted into single stranded and than into partially double-stranded DNA.
Pathogenesis
Hepatitis B virus (HBV) is a small DNA virus and belongs to a group of hepatotropic DNA viruses (hepadnaviruses)[1,2]. The virus consists of a nucleocapsid and an outer envelope composed mainly of three hepatitis B surface antigens (HBsAgs) that play a central role in the diagnosis of HBV infection. The nucleocapsid contains hepatitis B core antigen (HBcAg), a DNA polymerasereverse transcriptase, the viral genome as well as cellular proteins[1,2].
The genome consists of a partially double-stranded circular DNA molecule of about 3200 base pairs in length with known sequence as well as genetic organization. The pre-surface 1 [pre-S1]/pre-surface 2 [pre-S2]/and surface genes [S] code for the various HBsAgs. The protein encoded by the pre-core [pre-C]/core gene [C] undergoes post-translational modifi cation to yield hepatitis B e antigen (HBeAg), which is a seromarker for high viral replication[2]. The core gene codes for HBcAg, the major
structural protein of the nucleocapsid. Finally, the X gene codes for the hepatitis B x antigen (HBxAg).
Seronegative patients for HBeAg
Some patients have infection due HBV but are seronegative because they had a previous infection with some mutant virion encoding a pre-C/C mutant that has a translation stop codon and the new virions don’t express the HBeAg but still replicating and are functionally active. These seronegative patients may be in very states of hepatitis: fulminant hepatitis, chronic hepatitis, self-limiting and asymptomatic hepatitis.
Core promoters variants
One mutation on core promoter enhancer II at two distinct points is associated with more aggressive disease. This variation can elicit chronic hepatitis or fulminant hepatitis.
Immune response
Response is basically by CTL that can eliminate HBV using cytopathic mechanism stead the noncytopathic elimination using INF α, γ. This response is polyclonal and specific. Hence, in chronic disease most probably the CTL are anergic, exhausted or there is an abnormal situation that mute them like disease or mutation.
Replication
Replication of the hepadnaviral genome can broadly be divided into three phases: (1) Infectious virions contain in their inner icosahedral core the genome as a partially double-stranded, circular but not covalently closed DNA of about 3.2 kb in length (relaxed circular, or RCDNA); (2) upon infection, the RC-DNA is converted, inside the host cell nucleus, into a plasmid-like covalently closed circular DNA (cccDNA); (3) from the cccDNA, several genomic and subgenomic RNAs are transcribed by cellular RNA polymerase ; of these, the pregenomic RNA (pgRNA) is selectively packaged into progeny capsids and is reverse transcribed by the co-packaged P protein into new RC-DNA genomes. Matured RCDNA containing-but not immature RNA containingnucleocapsids can be used for intracellular cccDNA amplification, or be enveloped and released from the cell as progeny virions. Below we discuss these genome conversions, with emphasis on the reverse transcription step, and particularly its unique initiation mechanism.
Persistent viral infections require that the viral genome be present in the infected cell in a stable form that is not lost during cell division, and which therefore can be used for the continuous production of progeny genomes. For hepadnaviruses, the genome persists, instead, as a nuclear, episomal covalently closed circle, i.e. the cccDNA.
Distinct features of the RC-DNA (Figure 2) are (1), only the (-)-DNA strand (with opposite polarity to the mRNAs) is complete whereas the (+)-strands comprise a cohort of less than full-length molecules; (2), the 5´ end of the (-)-DNA is covalently linked to P protein; (3) the 5´
end of the (+)-strand consists of an RNA oligonucleotide, derived from the pgRNA, which served as the primer for (+)-strand synthesis. For cccDNA formation, all these modifi cations need to be removed, and both strands need to be covalently ligated.
The protein p is not related with RC-DNA conversion.
In transcription a few virions can have others transcripts different of PgRNA but they are unfunctional, the correct transcription is up to post-transcriptional regulatory element (PRE).
The Pg-RNA is mainly the mRNA for p protein and core proteins and second for new synthesis of RC-DNA. RNA polymerase can fail the transcription in an uncounted amount.
The Pg-RNA and p protein are encapsulated thanks to the epsilon union that allows the dimers of c protein to initiate the packing. This epsilon region (5’ Pg-RNA) contact ensures that the p protein starts the reverse transcription of the new - RC-DNA using the Pg-RNA. The capsids are essential for RC-DNA synthesis.
Oncogenesis
HCC (hepatocelular carcinoma) is more frecuent in men than in women. Chronic infection by HBV is a risk factor, others factors include: HCV chronic infection, aflatoxin b exposure, alcohol, obesity and diabetes.
HBV is found to be integrated in the host genoma frecuently, but there is not consistent data that ensures an oncogen activation.
HBxAg is a small protein that has been related with oncogenesis. Apparently, interferes with cell transcription, with p53, with DNA reparation, with normal signaling cascades of cell growing.
Pre-S2 activator proteins encompasses a group of proteins that can elicit HCC. Ths surface protein L has a Pre-S2 domain that can initiate a signaling cascade via PKC.
“…Immune pathogenesis of HCC
A major factor in the process of HBV-associated HCC development is the immune system[104,106,107]. The relevance of a chronic, virus-specific immune response for
development of HBV-associated carcinoma was shown in an elegant experiment from F. Chisari`s laboratory[108]. Transgenic mice that produce non-cytopathic amounts of
HBsAg were used. In these mice, immunologic tolerance against the transgene product can be observed. In accordance with this, no evidence of the liver disease was observed. These mice were subjected to thymectomy and lethally irradiated. One group was reconstituted with the
bone marrow and spleen cells derived from non-transgenic littermates that were vaccinated with a recombinant HBsAg encoding vaccinia virus resulting in HBsAgspecific cytotoxic T lymphocytes (CTLs) and antibodies. The other group was reconstituted with the bone marrow
and spleen cells derived from transgenic donors that were immunologically tolerant.
In this animal model, the development of hepatitis and later of chronic hepatitis and finally HCC development could be exclusively observed in the mice that were reconstituted with the bone marrow and spleen cells derived from the vaccinated non-transgenic animals, but
not in the control groups. Based on this, it was concluded that the immune system-mediated chronic inflammation of the liver, continuous cell death and subsequent cell proliferation might increase the frequency of genetic alterations and the risk of cáncer…”
In other words, the same T-cell response can have complete different effects: if the T cell response is strong enough, HBV can be eliminated from the liver, if not, a pro-carcinogenic
effect can be induced by permanently triggering necroinflammatory disease without resulting in a final eradication of HBV from the liver.
References: The world journal of gastroenterology
http://www.wjgnet.com
Morphology
The Shell is conformed by protein c which creates dimers of protein c. Then, the dimers unites into oligomers and can create 90 icosaedral capsomers (t=3) or 120 icosaedral capsomers (t=4).
The protein c is like an upside down “T” in wich the horizontal bar mediates the dimer conformation and the vertical bar forms a spike protruding outside the virion. This spike has an epitope HBcAg.
Envelope proteins
The three proteins S,M and L are transcripted by the same region because an ORF in one area call E. Depending on which codon of the three do use the cell. The protein S are synthesized in ER (E. reticulum) as a transmembrane protein with two segments and with the loop segment in the lumen of the ER N- glycosilated, this brings the HBsAg epitope, which is very immunogenic and is usually used in vaccination. With protein M occurs similar but Protein L can folde in two ways: one with the loop (containing Pre-S1) outside of the virion or another with the same inside. This last fact is functionally unknown.
During HBV nucleocapsid formation, the RNA pregenome is packaged into the particle’s lumen and first converted into single stranded and than into partially double-stranded DNA.
Pathogenesis
Hepatitis B virus (HBV) is a small DNA virus and belongs to a group of hepatotropic DNA viruses (hepadnaviruses)[1,2]. The virus consists of a nucleocapsid and an outer envelope composed mainly of three hepatitis B surface antigens (HBsAgs) that play a central role in the diagnosis of HBV infection. The nucleocapsid contains hepatitis B core antigen (HBcAg), a DNA polymerasereverse transcriptase, the viral genome as well as cellular proteins[1,2].
The genome consists of a partially double-stranded circular DNA molecule of about 3200 base pairs in length with known sequence as well as genetic organization. The pre-surface 1 [pre-S1]/pre-surface 2 [pre-S2]/and surface genes [S] code for the various HBsAgs. The protein encoded by the pre-core [pre-C]/core gene [C] undergoes post-translational modifi cation to yield hepatitis B e antigen (HBeAg), which is a seromarker for high viral replication[2]. The core gene codes for HBcAg, the major
structural protein of the nucleocapsid. Finally, the X gene codes for the hepatitis B x antigen (HBxAg).
Seronegative patients for HBeAg
Some patients have infection due HBV but are seronegative because they had a previous infection with some mutant virion encoding a pre-C/C mutant that has a translation stop codon and the new virions don’t express the HBeAg but still replicating and are functionally active. These seronegative patients may be in very states of hepatitis: fulminant hepatitis, chronic hepatitis, self-limiting and asymptomatic hepatitis.
Core promoters variants
One mutation on core promoter enhancer II at two distinct points is associated with more aggressive disease. This variation can elicit chronic hepatitis or fulminant hepatitis.
Immune response
Response is basically by CTL that can eliminate HBV using cytopathic mechanism stead the noncytopathic elimination using INF α, γ. This response is polyclonal and specific. Hence, in chronic disease most probably the CTL are anergic, exhausted or there is an abnormal situation that mute them like disease or mutation.
Replication
Replication of the hepadnaviral genome can broadly be divided into three phases: (1) Infectious virions contain in their inner icosahedral core the genome as a partially double-stranded, circular but not covalently closed DNA of about 3.2 kb in length (relaxed circular, or RCDNA); (2) upon infection, the RC-DNA is converted, inside the host cell nucleus, into a plasmid-like covalently closed circular DNA (cccDNA); (3) from the cccDNA, several genomic and subgenomic RNAs are transcribed by cellular RNA polymerase ; of these, the pregenomic RNA (pgRNA) is selectively packaged into progeny capsids and is reverse transcribed by the co-packaged P protein into new RC-DNA genomes. Matured RCDNA containing-but not immature RNA containingnucleocapsids can be used for intracellular cccDNA amplification, or be enveloped and released from the cell as progeny virions. Below we discuss these genome conversions, with emphasis on the reverse transcription step, and particularly its unique initiation mechanism.
Persistent viral infections require that the viral genome be present in the infected cell in a stable form that is not lost during cell division, and which therefore can be used for the continuous production of progeny genomes. For hepadnaviruses, the genome persists, instead, as a nuclear, episomal covalently closed circle, i.e. the cccDNA.
Distinct features of the RC-DNA (Figure 2) are (1), only the (-)-DNA strand (with opposite polarity to the mRNAs) is complete whereas the (+)-strands comprise a cohort of less than full-length molecules; (2), the 5´ end of the (-)-DNA is covalently linked to P protein; (3) the 5´
end of the (+)-strand consists of an RNA oligonucleotide, derived from the pgRNA, which served as the primer for (+)-strand synthesis. For cccDNA formation, all these modifi cations need to be removed, and both strands need to be covalently ligated.
The protein p is not related with RC-DNA conversion.
In transcription a few virions can have others transcripts different of PgRNA but they are unfunctional, the correct transcription is up to post-transcriptional regulatory element (PRE).
The Pg-RNA is mainly the mRNA for p protein and core proteins and second for new synthesis of RC-DNA. RNA polymerase can fail the transcription in an uncounted amount.
The Pg-RNA and p protein are encapsulated thanks to the epsilon union that allows the dimers of c protein to initiate the packing. This epsilon region (5’ Pg-RNA) contact ensures that the p protein starts the reverse transcription of the new - RC-DNA using the Pg-RNA. The capsids are essential for RC-DNA synthesis.
Oncogenesis
HCC (hepatocelular carcinoma) is more frecuent in men than in women. Chronic infection by HBV is a risk factor, others factors include: HCV chronic infection, aflatoxin b exposure, alcohol, obesity and diabetes.
HBV is found to be integrated in the host genoma frecuently, but there is not consistent data that ensures an oncogen activation.
HBxAg is a small protein that has been related with oncogenesis. Apparently, interferes with cell transcription, with p53, with DNA reparation, with normal signaling cascades of cell growing.
Pre-S2 activator proteins encompasses a group of proteins that can elicit HCC. Ths surface protein L has a Pre-S2 domain that can initiate a signaling cascade via PKC.
“…Immune pathogenesis of HCC
A major factor in the process of HBV-associated HCC development is the immune system[104,106,107]. The relevance of a chronic, virus-specific immune response for
development of HBV-associated carcinoma was shown in an elegant experiment from F. Chisari`s laboratory[108]. Transgenic mice that produce non-cytopathic amounts of
HBsAg were used. In these mice, immunologic tolerance against the transgene product can be observed. In accordance with this, no evidence of the liver disease was observed. These mice were subjected to thymectomy and lethally irradiated. One group was reconstituted with the
bone marrow and spleen cells derived from non-transgenic littermates that were vaccinated with a recombinant HBsAg encoding vaccinia virus resulting in HBsAgspecific cytotoxic T lymphocytes (CTLs) and antibodies. The other group was reconstituted with the bone marrow
and spleen cells derived from transgenic donors that were immunologically tolerant.
In this animal model, the development of hepatitis and later of chronic hepatitis and finally HCC development could be exclusively observed in the mice that were reconstituted with the bone marrow and spleen cells derived from the vaccinated non-transgenic animals, but
not in the control groups. Based on this, it was concluded that the immune system-mediated chronic inflammation of the liver, continuous cell death and subsequent cell proliferation might increase the frequency of genetic alterations and the risk of cáncer…”
In other words, the same T-cell response can have complete different effects: if the T cell response is strong enough, HBV can be eliminated from the liver, if not, a pro-carcinogenic
effect can be induced by permanently triggering necroinflammatory disease without resulting in a final eradication of HBV from the liver.
References: The world journal of gastroenterology
http://www.wjgnet.com
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