Hepatitis Type B
المؤلف:
Stefan Riedel, Jeffery A. Hobden, Steve Miller, Stephen A. Morse, Timothy A. Mietzner, Barbara Detrick, Thomas G. Mitchell, Judy A. Sakanari, Peter Hotez, Rojelio Mejia
المصدر:
Jawetz, Melnick, & Adelberg’s Medical Microbiology
الجزء والصفحة:
28e , p511-515
2025-11-30
85
HBV is classified as a hepadnavirus (Table 1). HBV establishes chronic infections, especially in those infected as infants; it is a major factor in the eventual development of liver disease and hepatocellular carcinoma in those individuals.
Table1. Important Properties of Hepadnavirusesa
A. Structure and Composition
Electron microscopy of hepatitis B surface antigen (HBsAg) positive serum reveals three morphologic forms (Figures 1 and 2A). The most numerous are spherical particles measuring 22 nm in diameter (Figure 2B). These small particles are made up exclusively of HBsAg—as are tubular or filamentous forms, which have the same diameter but may be more than 200 nm long—and result from overproduction of HBsAg. Larger, 42-nm spherical virions (originally referred to as Dane particles) are less frequently observed (see Figure 1). The outer surface, or envelope, contains HBsAg and surrounds a 27-nm inner nucleocapsid core that contains hepatitis B core antigen (HBcAg) (Figure 2C). The variable length of a single-stranded region of the circular DNA genome results in genetically heterogeneous particles with a wide range of buoyant densities.
Fig1. Hepatitis B viral and subviral forms. A: Schematic representation of three hepatitis B surface antigen (HBsAg) containing forms that can be identified in serum from hepatitis B virus (HBV) carriers. The 42-nm spherical Dane particle can be disrupted by nonionic detergents to release the 28-nm core that contains the partially double-stranded viral DNA genome. A soluble antigen, termed hepatitis B e antigen (HBeAg), may be released from core particles by treatment with strong detergent. HBcAg, hepatitis B core antigen. B: Electron micrograph showing three distinct HBsAg-bearing forms: 20-nm pleomorphic spherical particles (A), filamentous forms (B), and 42-nm spherical Dane particles, the infectious form of HBV (C). (Courtesy of FB Hollinger.)
Fig2. A: Unfractionated hepatitis B surface antigen (HBsAg)-positive human plasma. Filaments, 22-nm spherical particles, and a few 42-nm virions are shown (77,000 ×). B: Purified HBsAg (55,000 ×). (Courtesy of RM McCombs and JP Brunschwig.) C: Hepatitis B core antigen purified from infected liver nuclei (122,400 ×). The diameter of the core particles is 27 nm. (Courtesy of HA Fields, GR Dreesman, and G Cabral.)
The viral genome (Figure 3) consists of partially double-stranded circular DNA, 3200 bp in length. Different HBV isolates share 90–98% nucleotide sequence homology. The full-length DNA minus strand (L or long strand) is complementary to all HBV mRNAs; the positive strand (S or short strand) is variable and between 50% and 80% of unit length.
Fig3. Genetic organization of the hepatitis B virus genome. Four open reading frames encoding seven peptides are indicated by large arrows. Regulatory sequences (promoters [prom], enhancers [Enh], and glucocorticoid-responsive element [GRE]) are marked. Only the two major transcripts (core/pre-genome and S mRNAs) are represented. DR1 and DR2 are two directly repeated sequences of 11 bp at the 5′ extremities of the minus- and plus-strand DNA. (Reproduced with permission from Buendia MA: Hepatitis B viruses and hepatocellular carcinoma. Adv Cancer Res 1992;59:167. Academic Press, Inc.)
There are four open reading frames that encode seven polypeptides. These include structural proteins of the virion surface and core, a small transcriptional transactivator (X), and a large polymerase (P) protein that includes DNA polymerase, reverse transcriptase, and RNase H activities. The S gene has three in-frame initiation codons and encodes the major HBsAg, as well as polypeptides containing in addition pre-S2 or pre-S1 and pre-S2 sequences. The C gene has two in-frame initiation codons and encodes HBcAg plus the HBe protein, which is processed to produce soluble hepatitis B e antigen (HBeAg).
The particles containing HBsAg are antigenically com plex. Each contains a group-specific antigen, a, in addition to two pairs of mutually exclusive subdeterminants, d/y and w/r. Thus, four phenotypes of HBsAg have been observed: adw, ayw, adr, and ayr. In the United States, adw is the pre dominant subtype. These virus-specific markers are useful in epidemiologic investigations because secondary cases have the same subtype as the index case.
The stability of HBsAg does not always coincide with that of the infectious agent. However, both are stable at −20°C for more than 20 years and stable to repeated freezing and thawing. The virus also is stable at 37°C for 60 minutes and remains viable after being dried and stored at 25°C for at least 1 week. HBV (but not HBsAg) is sensitive to higher temperatures (100°C for 1 minute) or to longer incubation periods (60°C for 10 hours). HBsAg is stable at a pH of 2.4 for up to 6 hours, but HBV infectivity is lost. Sodium hypochlorite, 0.5% (eg, 1:10 chlorine bleach), destroys antigenicity within 3 minutes at low protein concentrations, but undiluted serum specimens require higher concentrations (5%). HBsAg is not destroyed by ultraviolet irradiation of plasma or other blood products, and viral infectivity may also resist such treatment.
B. Replication of Hepatitis B Virus
The infectious virion attaches to cells and becomes uncoated (Figure 4). In the nucleus, the partially double-stranded viral genome is converted to covalently closed circular double stranded DNA (cccDNA). The cccDNA serves as template for all viral transcripts, including a 3.5-kb pregenome RNA. The pregenome RNA becomes encapsidated with newly synthesized HBcAg. Within the cores, the viral polymerase synthesizes by reverse transcription a negative-strand DNA copy. The polymerase starts to synthesize the positive DNA strand, but the process is not completed. Cores bud from the pre-Golgi mem branes, acquiring HBsAg containing envelopes, and may exit the cell. Alternatively, cores may be reimported into the nucleus and initiate another round of replication in the same cell.
Fig4. Hepatitis B virus (HBV) replication cycle. HBV attachment to a receptor on the surface of hepatocytes occurs via a portion of the pre-S region of hepatitis B surface antigen (HBsAg). After uncoating of the virus, unidentified cellular enzymes convert the partially double-stranded DNA to covalent closed circular (ccc) DNA that can be detected in the nucleus. The cccDNA serves as the template for the production of HBV mRNAs and the 3.5-kb RNA pre genome. The pre-genome is encapsidated by a packaging signal located near the 5′ end of the RNA into newly synthesized core particles, where it serves as template for the HBV reverse transcriptase encoded within the polymerase gene. An RNase H activity of the polymerase removes the RNA template as the negative-strand DNA is being synthesized. Positive-strand DNA synthesis does not proceed to completion within the core, resulting in replicative intermediates consisting of full-length minus-strand DNA plus variable-length (20–80%) positive-strand DNA. Core particles containing these DNA replicative intermediates bud from pre-Golgi membranes (acquiring HBsAg in the process) and may either exit the cell or reenter the intracellular infection cycle. (Reproduced with permission from Butel JS, Lee TH, Slagle BL: Is the DNA repair system involved in hepatitis-B-virus-mediated hepatocellular carcinogenesis? Trends Microbiol 1996;4:119.)
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