Hepatitis B Virus (HBV):

'Serum hepatitis' was distinguished clinically from 'infectious hepatitis' in the 1930's indicating that at least at least 2 different infectious agents were responsible for hepatitis. Infection often results from inoculation with human serum - blood transfusions, transplants or passive immunization (common among IVDAs). However, the virus is also transmitted sexually, by ingestion and from mother to child (transplacenta and breast milk) - accounting for familial clusters. All blood/organ/tissue donations in developed countries are now tested for HBV and risk of transmission is extremely low. Incubation period 45-120 days. HBV does not grow in tissue culture and this has hindered investigations.

HBV is the prototype member of the family Hepadnaviridae.

Features:

HBV particle

Spherical, enveloped (? lipid-containing, detergent disrupted ?) particles 42-47nm diameter containing partially d/s DNA plus an RNA-dependent DNA polymerase (i.e. reverse transcriptase)
(c.f. retroviruses - package RNA + RT).

Hepadnaviruses have the among the smallest genomes of all known viruses, consisting of two uneven strands of DNA:

(-)sense strand, 3.0 - 3.3kb (size varies between different Hepadnaviruses)
(+)sense strand, 1.7 - 2.8kb (size varies between different particles)

Replication:

 HBsAg is composed of 3 polypeptides (below) and is presumably responsible for receptor binding (not known), which in turn presumably determines the tropism of the virus for hepatocytes (not known). 3 major genome transcripts are produced: 3.5kb, 2.4kb, 2.1kb. All have same polarity, same 3' ends but different 5' ends (i.e. initiation sites). These transcripts are somewhat heterogeneous in size and it is not completely clear which proteins each transcript encodes, but there are 4 known genes in the virus:

Closed circular DNA is found soon after infection in the nucleus of the cell and therefore is probably the source of these transcripts. This DNA is produced by repair of the gapped virion DNA as follows:

  1. completion of the (+)sense strand
  2. removal of a protein primer from the (-)sense strand and an oligoribonucleotide primer from the (+)sense strand
  3. elimination of terminal redundancy at the ends of the (-)sense strand
  4. ligation of the ends of the two strands

It is not known how or by which proteins (viral/cellular) these events are carried out. The 3.5kb RNA transcript, core antigen and polymerase form core particles in the cytoplasm. The polymerase converts the RNA to DNA in these particles INSIDE THE PARTICLE in the cytoplasm c.f. retroviruses, where RNA is packaged then converted to DNA as the first stage of genome replication:

Features: Hepadnaviruses: Retroviruses:
Genome: DNA RNA
Primer for (-)strand synthesis: Protein tRNA
Terminal Repeats (LTRs): No Yes
Specific integration site in virus genome: No Yes

The surface antigen and lipid envelope may be acquired at any stage after encapsidation of the RNA, apparently from intracellular membranes.

Assembly/release appear to be rather disordered events for Hepadnaviruses - some extracellular particles contain DNA-RNA hybrids or (-)sense DNA strands without (+)sense strands (intermediates in reverse transcription). Assembly of the particle is initiated by packaging of the RNA pregenome and the viral reverse transcriptase-DNA polymerase into a nucleocapsid. The pregenome is then reverse transcribed into single-stranded minus-polarity DNA, which is subsequently replicated to double-stranded DNA. All replicative intermediates are observable in capsids within infected liver, but only relatively mature nucleocapsids containing partially double stranded DNA are found in secreted virions. This observation suggests that maturation of the genome within the capsid is required for envelopment and secretion.
Release of mature particles occurs by secretory mechanisms - "reverse endocytosis", without cell lysis.

Pathogenesis:

HBV infection has 3 possible outcomes:
  1. Acute course with complete recovery and immunity from reinfection (>90%).
  2. Fulminant hepatitis with liver failure and mortality ~90% (~1% cases).
  3. Chronic infection - carrier state with virus persistence (~10% cases).
There are >200m HBV carriers worldwide (total population of world ~4bn. = 5%).

Primary Hepatocellular Carcinoma (PHC): A rare tumour in the west (<2% fatal cancers) and most cases are alcohol-related. In S.E. Asia and China PHC is the most common fatal cancer, ~5x105 deaths p.a.
Relationship between HBV infection and PHC is not clear cut: The key factor is then what determines the development of chronic vs. acute infection:

Prevention/Therapy:

Purified (!) HBsAg from the blood of chronic carriers was originally used as a vaccine - risky! A recombinant HBsAg vaccine produced in yeast is now used - safe and reasonably effective - one of the few recombinant vaccines to date. Effective vaccination campaigns could:
  1. save ~1m lives p.a.
  2. eradicate the virus (no animal reservoir).

Alpha-IFN is used for therapy of chronic HBV infection. 30-40% chronic carriers respond to this (expensive) treatment, c.f. 10-20% spontaneous loss of virus markers in untreated control groups.
Lamivudine (3TC - 2'deoxy, 3'thiacytidine - a reverse transcriptase inhibitor) is currently being investigated for therapy of chronic HBV infection. Early results suggest this drug may be effective in patients who have previously failed to clear the virus with alpha-IFN.
A number of other drugs and a therapeutic vaccine are also in clinical trials. Read: Terrault, N.A. "Treatment of chronic hepatitis B and chronic hepatitis C" Rev.Med.Virol. 6:215-228 (1996).

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© AJC 1998