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Hepatitis B virus

CDC website: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_b/slide_1.htm


Key Features of Hepatitis B Virus Relevance • 250 million people infected worldwide. • In areas of Africa and East Asia, 50% of the population may be seropositive, 5-15% may be chronically infected (carriers). • Carriers are 200x more likely than non-carriers to develop primary hepatocellular carcinoma. • 300,000 cases per year in the US; 4,000 fatalities. 70-90% of maternal-neonatal infections result in chronic infection.


Key Features of Hepatitis B Virus

• Enveloped virion containing partial double-stranded circular DNA genome • Replication occurs through an RNA intermediate •

Virus encodes and carries a reverse transcriptase

• Virus encoded several antigenically and clinically predictive important proteins


Key Features of Hepatitis B Virus

• Virus has a strict tissue tropism to the liver • Virus infected cells produce and release large amounts of HBsAg particles lacking DNA • Viral DNA can integrate into the host chromosome


Hepatitis B Virion, Dane particle and HBsAG

From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,


Nomenclature for Hepatitis B Virus components


Transcription of Hepatitis B virus

Figure 43-1

From Engleberg, et. al., Schaechter’s Mechanisms of Microbial Disease, Fourth Edition, Chapter 43, published by Lippincott Williams & Wilkins, Philadelphia.


The growth cycle of Hepatitis B virus

From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,

Figure 66-5


Reverse transcription of Hepadnavirus occurs with packaging of pre-genomic RNA FIGURE 43-3 Hepatitis B virus genome replication. 1. Reverse transcription begins with the polymerase binding to a unique stem-loop structure, located at the 5′ end of pregenomic RNA. 2. The polymerase (P) uses one of its own amino acids to prime synthesis and copies three or four nucleotides derived from a bulged region of the stem-loop structure (2a). The polymerase then translocates to the 3′ copy of direct repeat 1 (DR1), which includes nucleotides that are complementary to those attached to the polymerase (2b). 3. Reverse transcription is extended from that point. As the leading front of the polymerase copies RNA into DNA, its trailing portion destroys the template that has already been copied. 4. When the polymerase reaches the 5′ end of the pregenomic RNA, minus-strand synthesis is complete. The short pregenomic RNA oligonucleotide that remains undigested is then used to prime plus-strand DNA synthesis. That RNA includes the 5′ copy of DR1 and is translocated to a new and complementary region near the 5′ end of the minus DNA strand termed direct repeat 2 (DR2). 5. Once the second translocation has occurred, plus-strand synthesis begins. During plus-strand synthesis, when the polymerase reaches the end of the minus-strand template, a third and final translocation event occurs. The minus DNA strand has two small terminal redundancies, termed メ r モ . 6. The 5′ copy of r is dissociated from the plus DNA strand and replaced with the 3′ copy. That dissociation results in the circularization of the DNA molecule and enables further extension of the plus strand cap, 5′-terminal cap; An, poly(A) tract.

From Engleberg, et. al., Schaechter’s Mechanisms of Microbial Disease, Fourth Edition, Chapter 43, published by Lippincott Williams & Wilkins, Philadelphia.


Hepatitis B - Clinical Features  Incubation period:  Clinical illness (jaundice):  Acute case-fatality rate:  Chronic infection:  Premature mortality from chronic liver disease:

Average 60-90 days Range 45-180 days <5 yrs, <10% 5 yrs, 30%-50% 0.5%-1% <5 yrs, 30%-90% 5 yrs, 2%-10% 15%-25%


Prevalence of Hepatitis B carriers

Figure 66-9. Worldwide prevalence of hepatitis B carriers and primary hepatocellular carcinoma. (Courtesy Centers for Disease Control and Prevention, Atlanta.) From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,


Clinical outcomes of Hepatitis B infections

Figure 66-11. Clinical outcomes of acute hepatitis B infection. (Redrawn from White DO, Fenner F: Medical virology, ed 3, New York, 1986, Academic Press From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 62, published by Mosby Philadelphia,,


Immunological events of acute vs. chronic HBV infection A) Acute

B) Chronic

From Engleberg, et. al., Schaechterâ&#x20AC;&#x2122;s Mechanisms of Microbial Disease, Fourth Edition, Chapter 43, published by Lippincott Williams & Wilkins, Philadelphia.


Clinical interpretation of the Hepatitis B antigen panel

CDC WEB site: http://www.cdc.gov/ncidod/diseases/hepatitis/b/Bserology.htm


Determinants or acute and chronic HBV infection

Figure 66-7

From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,


Prevention of Hepatitis B â&#x20AC;&#x201C;prophylaxis and vaccination


The HIV and Hepatitis B Reverse Transcription Systems

Flint, S.J., Enquist, L.W. et. al., “Principles of Virology”ASM Press, 2000, Chapter 7


CDC website: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_d/slide_1.htm

Notes: HDV infection can be acquired either as a co-infection with HBV or as a superinfection of persons with chronic HBV infection. Persons with HBV-HDV co-infection may have more severe acute disease and a higher risk of fulminant hepatitis (2%-20%) compared with those infected with HBV alone; however, chronic HBV infection appears to occur less frequently in persons with HBV-HDV co-infection. Chronic HBV carriers who acquire HDV superinfection usually develop chronic HDV infection. In long-term studies of chronic HBV carriers with HDV superinfection, 70%80% have developed evidence of chronic liver diseases with cirrhosis compared with 15%-30% of patients with chronic HBV infection alone.


Key features of Hepatitis Delta Virus •Single stranded, self complementary RNA, encapsidated in HbsAg •Small, amorphous particle •RNA encodes one protein: delta antigen •Replicates via RNA directed RNA synthesis, catalyzed by host RNA polymerase II


Key features of Hepatitis Delta Virus •Delta antigen required for replication, role unknown •Dependent on HBV as a “helper” •HBV provides HbsAg •May be acquired as co-infection with HBV, or superinfection of HBV infection •Exacerbates HBV induced disease


Hepatitis Delta Virion

Figure 66-14

From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,


Consequences of hepatitis B and delta virus infection

Figure 66-15. Consequences of deltavirus infection. Deltavirus (d) requires the presence of hepatitis B virus (HBV) infection. Superinfection of a person already infected with HBV (carrier) causes more rapid, severe progression than co-infection (shorter arrow).

From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia.


The HDV genome

Figure 88-4 Structure of the HDV RNA Genome. The single-stranded circular RNA genome is indicated by the heavy black continuous line. The genome has the ability to form an unbranched rod structure, in which approximately 70% of the bases are engaged in Watson-Crick pairs with counterparts from the opposite side of the circular RNA. In this unbranched rod structure, the region encoding HDAg (nt 1598-957) is on one side. The RNA editing site is at position 1012 in the antigenome. The region on the right-hand side contains the autocatalytic cleavage sites (ribozymes), one in the genome (nt 686) and the other in the antigenome (nt 900). The genome binds HDAg and is transcribed by a host DNA窶電ependent RNA polymerase.

Fields Virology 4th edition, 2002, Chapter 88, Lippincott, Williams and Wilkins, 2002 Fig. 88-4


CDC Website: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_d/slide_6.htm


Diagnosis 

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A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection. HBsAg - used as a general marker of infection. HBsAb - used to document recovery and/or immunity to HBV infection. anti-HBc IgM - marker of acute infection. anti-HBcIgG - past or chronic infection. HBeAg - indicates active replication of virus and therefore infectiveness. Anti-Hbe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV. HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

Wong’s virology WEB site: http://virologyonline.com/presentations/hepatitis.htm


Hepatitis B acute infection

Note: Pattern of serological markers varies depending on whether the infection if acute or chronic

CDC website: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_b/slide_3.htm


Chronic Hepatitis B infection

Notes: In patients with chronic HBV infection, both HBsAg and IgG anti-HBc remain persistently detectable, generally for life. HBeAg is variably present in these patients. The presence of HBsAg for 6 months or more is generally indicative of chronic infection. In addition, a negative test for IgM anti-HBc together with a positive test for HBsAg in a single serum specimen usually indicates that an individual has chronic HBV infection.

http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_b/slide_4.htm


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