The Oncologist, Vol. 12, No. 5, 516-517, May 2007; doi:10.1634/theoncologist.12-5-516
© 2007 AlphaMed Press
The Molecular Perspective: Hepatitis B Virus
David S. Goodsell
The Scripps Research Institute, La Jolla, California, USA
Correspondence: David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu; Website: http://www.scripps.edu/pub/goodsell
Received April 4, 2007;
accepted for publication April 4, 2007.
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Learning Objectives
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After reading this article, the reader will be able to:- Discuss the hepatitis B virus and its role in carcinogenesis.
Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com
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INTRODUCTION
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Viruses are remarkable for their economy: it is often hard to imagine how so much trouble can be packed into such a small object. Hepatitis B virus is no exception. It is barely 50 nanometers across—just over twice the diameter of a ribosome—and encodes only a handful of proteins in its small genome of about 3,000 DNA nucleotides. But with this modest arsenal, the virus manages to evade the immune system and attack liver cells, leading to hepatitis and, in some cases, cancer.
Hepatitis B virus, shown in Figure 1, is composed of several layers. Outermost, there is a membrane envelope, picked up when the virus buds from an infected cell. The membrane is studded with three similar forms of an envelope protein. These envelope proteins search for cells to infect, attaching to a yet-unknown receptor on the liver cell surface. Inside the membrane, there is a protein capsid, as shown in Figure 2. As with many viral capsids, it is formed of a single type of protein, which associates to form a hollow shell with icosahedral symmetry. The most common form of hepatitis B virus contains a capsid composed of 240 capsid proteins, but about 10% have a smaller capsid comprised of 180 proteins.
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Figure 1. Hepatitis B virus. A mature virus is shown at the bottom in cross section, to show the multilayered structure. The outer envelope is shown in purple, the capsid is shown in blue, and on the inside, the DNA is in yellow and the reverse transcriptase is in red. A subviral particle, studded with envelope proteins, is shown at the top in purple. The two particles are surrounded by proteins in the blood serum, including many Y-shaped antibodies.
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Figure 2. Hepatitis B viral capsid. The atomic structure of the viral capsid has been determined by x-ray crystallography, revealing an unusual spiked structure composed of 240 protein subunits. The capsid has many large holes, which allow nucleotides to enter and exit during the reverse transcription of the viral genome. Coordinates were taken from entry 1qgt at the Protein Data Bank (http://www.pdb.org).
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The inner workings of the virion, which includes the DNA genome and a reverse transcriptase enzyme, are unusual. In most copies of the virus, the genome is composed of one complete DNA strand that is held in a big loose circle by a partial second strand. This odd genome—part single strand and part double helix—is a consequence of the method by which the virus replicates. In the cell, a long RNA copy of the genome is packaged into a new capsid, then the reverse transcriptase gets to work and copies it into the DNA form of the mature infectious virion. Construction of the second strand may halt when the capsid gets too crowded, stopping short of a full-length double helix. Alternatively, the formation of double-stranded DNA appears to be the signal that causes the capsid to seek out the membrane and start budding out of the cell. So, reverse transcription may be halted prematurely when the supply of nucleotides is shut off as the virus buds. Either way, the reverse transcriptase rarely completes its job of making a complete double-stranded copy of the genome.
Hepatitis B virus also has an unusual mechanism for fighting the immune system. Infected cells are forced to build new viruses, but they also construct smaller virus-like particles that contain no DNA. The infected cell floods the blood with these small subviral particles and they sop up the antibodies that are waiting to attack the viruses. Infected individuals may have trillions of these little decoys in every milliliter of blood. The method, however, has backfired in recent times, since a very similar particle, made by recombinant DNA technology, is now used as a vaccine against the virus.
In many cases, infection by hepatitis B virus is cleared naturally by the immune system. But in some cases, chronic infection occurs, with dire consequences. In particular, chronic infection is one of the leading causes of hepatocellular carcinoma. The mechanism is still debated. It may be due directly to the process of viral replication, perhaps caused by integration of the viral genome in inopportune places or perhaps caused by the oncogenic effect of the small viral protein X or other viral proteins. Alternatively, the long-term effect of continually destroying infected cells and replacing them, as the body uses harsh methods to fight the chronic infection, may lead to an increased chance of forming a cancerous cell.
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ADDITIONAL READING
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- Glebe D, Topic highlight: Hepatitis B virus. World J Gastroenterol 2007;13:8–140.[Medline]
- Seeger C, Zoulin F, Mason WS. Fields Virology. Hepadnaviruses. Fifth Edition. Philadelphia: Wolters Kluwer Lippincott Williams and Wilkins, 2007:2977-3023.
- Dryden KA, Wieland SF, Whitten-Bauer C et al. Native hepatitis B virions and capsids visualized by electron cryomicroscopy. Mol Cell 2006;22:843–850.[CrossRef][Medline]
- Gilbert RJC, Beales L, Blond D et al. Hepatitis B small surface antigen particles are octahedral. Proc Natl Acad Sci U S A 2005;102:14783–14788.[Abstract/Free Full Text]
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Learning Objectives
Introduction