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 Note: HBeAg (E) is encoded in C region using different start codons and is not shown From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,, Figure 66-6

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 86-7 The hepadnaviral reverse transcription pathway. Pregenomic RNA (dashed line, step 1) is capped and polyadenylated and has a large terminal redundancy (R). The locations of direct repeats 1 and 2 (DR1 and DR2) are shown as correspondingly numbered boxes, and the e stem-loops are indicated. Pregenomic RNA packaging into cores is initiated by the interaction of P protein with the 5´ copy of e. P initiates reverse transcription at the 5´ stem-loop and extends negative-stranded DNA (solid line) for 3 to 4 nucleotides (step 2a). P and the covalently attached nascent DNA are then transferred to the 3´ copy of DR1 (step 2b), and the DNA is extended. During negative-stranded elongation, pgRNA is degraded by the RNaseH activity of P (step 3). When P reaches the 5´ end of the template, its RNaseH activity leaves an RNA oligomer consisting of r plus DR1 sequences (step 4). This RNA oligomer is translocated and annealed to DR2, where it primes positive-stranded DNA synthesis (lower solid line, step 5). Positive-stranded elongation proceeds to the 5´ end of the negative-stranded DNA template, including the sequences denoted as r. Because complementary r sequences are found at the 3´ end of negative-strandeds DNA, a second homology-mediated template transfer can now circularize the genome. The positive strand is then extended for a variable length (step 6) to yield mature viral DNA. Fields Virology 4th edition, 2002, Chapter 86, Lippincott, Williams and Wilkins, 2002 Fig. 86-7

Hepatitis B - Clinical Features Incubation period: Average 60-90 days Range 45-180 days Clinical illness (jaundice): <5 yrs, <10% 5 yrs, 30%-50% Acute case-fatality rate: 0.5%-1% Chronic infection: <5 yrs, 30%-90% 5 yrs, 2%-10% Premature mortality from chronic liver disease: 15%-25% 29

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 Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby 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 From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,, Figure 66-7

Prevention of Hepatitis B –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 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 From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,, Figure 66-14

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

CDC Website: http://www. cdc

Diagnosis 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://virology-online.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