This review article examines the structure and replication cycle of hepatitis B virus and discusses the natural history of primary infection, the mechanisms of clearance of the virus, and reasons for persistent infection. It concludes with a discussion of what we know about the virus and how it causes hepatitis and the implications for treatment.

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Hepatitis B Virus Infection — Natural History and Clinical Consequences

DNA recombinant technology has radically changed hepatitis B virus (HBV) virology. The genetic organization, transcription and replication of the virus are basically understood, structures of integrated HBV sequences in hepatocellular carcinoma have been characterized, and new vaccines produced by recombinant DNA technique are being developed.

The hepatitis B virus

A novel DNA virus (TTV) associated with elevated transaminase levels in posttransfusion hepatitis of unknown etiology.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(09)60207-5.pdf

Hepatitis B virus infection.

The complete nucleotide sequences of the DNA of three hepatitis B virus (HBV) genomes of subtype adw, cloned from plasma samples of asymptomatic carriers living in the mainland and Okinawa Prefecture of Japan and Indonesia were determined. All three comprised 3215 bp and differed in sequence by only 3.9 to 5.6%. When these isolates were compared with the reported sequences of two HBV genomes of the same subtype derived from American carriers, however, the differences were greater (8.3 to 9.3% to an extent comparable with the nucleotide divergence between an HBV genome of subtype adw and that of a heterotypic subtype, such as adr, ayw or ayr. A total of 18 HBV genomes of various subtypes, including the three described here, 10 reported previously and five unpublished ones, were classified into four groups based on an inter-group divergence in nucleotide sequence of 8% or greater: group A (two adw genomes), group B (four adw), group C (three adw, four adr and one ayr) and group D (four ayw). Thus, the nine genomes of HBV subtype adw were distributed into three groups with considerably different sequences. These results indicate that the four major antigenically defined subtypes of envelope polypeptide do not reflect true genotypic variation of HBV. The fact that d to y, as well as w to r, subtypic change can be induced by an A----G point mutation at nucleotides 365 and 479 in the S gene, respectively, supports this view.

Typing Hepatitis B Virus by Homology in Nucleotide Sequence: Comparison of Surface Antigen Subtypes

Testing of serum samples of 23 pregnant women who were asymptomatic carriers of hepatitis B surface antigen for e antigen and antibody to e with an immunodiffusion technic identified 10 mothers with e antigen and seven with e antibody. Their babies were tested for hepatitis B surface antigen in serum at intervals for more than 12 months. In all 10 babies born to e-antigen-positive mothers hepatitis B surface antigen developed and persisted through the observation period, and all 10 elder siblings of these newborn babies were found to be asymptomatic carriers. In remarkable contrast, all seven babies born to mothers positive for antibody to e escaped antigenemia, and none of their three elder siblings carried surface antigen. On the basis of these results, e antigen may be used as an indicator of transmission, and antibody to e as that of absence of transmission of hepatitis B virus from carrier mothers to children. (N Engl J Med 294: 746–749, 1976)

E Antigen and Anti-E in the Serum of Asymptomatic Carrier Mothers as Indicators of Positive and Negative Transmission of Hepatitis B Virus to Their Infants

Transfusion-transmitted hepatitis E caused by apparently indigenous hepatitis E virus strain in Hokkaido, Japan.

Hepatitis B e antigen (HBeAg) constitutes the nucleocapsid of hepatitis B virus (HBV) and occurs in association with plasma proteins, particularly with IgG, in the serum of persons infected with the virus. A polypeptide with an approximate m.w. of 15,500 (P15.5) is obtained either from HBeAg in the serum or from the nucleocapsid of HBV. P15.5 preparations from serum and virus resembled closely each other in the amino acid composition. The C-terminus amino acid sequence of P15.5 from serum was determined to be -Thr-Thr-Val-Val, whereas that from the virus ended with -Thr-Thr. The same sequence of four amino acid residues was found on the gene coding for the nucleopeptide of hepatitis B virus with a molecular size of 19,000 daltons (P19). P15.5 identified on the nucleotide sequence of P19 was composed of 149 amino acid residues with a calculated molecular size of 16,770 daltons. The gene coding for P19 had two -Asp-Pro-connections. By splitting these connections in P19 and P15.5 preparations with formic acid, smaller polypeptides were obtained with sizes predicted from the nucleotide sequence and with the N-terminus amino acid of proline as expected. One of two monoclonal antibodies raised against the core of Dane particles (HBcAg) bound with P15.5 preparations purified from serum and HBV. The IgG fraction from a human serum containing antibodies to HBcAg but not to HBeAg bound with P15.5 also. On the basis of the results obtained, the IgG molecules associated with P15.5 in the serum of persons infected with HBV may well represent the antibodies against HBcAg with limited specificities.

Immunochemical structure of hepatitis B e antigen in the serum.

Dane particles were isolated in a large scale from plasma of asymptomatic carriers of hepatitis B surface antigen. The core of Dane particles was exposed by treatment with NP-40 and 2-mercaptoethanol. The antigenicity of hepatitis B e antigen (HB e Ag) was not detected on the surface of Dane particles or of their cores. However, when Dane particle cores were treated with Pronase, some activity of HB e Ag was liberated from them as a small molecule. When the cores were further treated with SDS, they revealed a high activity of HB e Ag, indicating that HB e Ag existed in the core of Dane particles in a cryptic form, which can be exposed by treatment with proteolytic enzyme or SDS. Dane particles and their cores were subjected to polyacrylamide gel electrophoresis in SDS. After electrophoresis, the gel was cut into two halves, and each half was determined for polypeptide composition and for HB e Ag activity. Both of Dane particles and their cores disclosed two peaks of HB e Ag activity associated with molecules with a size of 19,000 and 45,000 daltons. These two polypeptides were the major constituents of the cores. Dane particles revealed several polypeptides in addition to the HB e Ag polypeptides, which were identified as hepatitis B surface antigen components. On the basis of the results obtained, HB e Ag is an integral component of Dane particles, the presently accepted hepatitis B virions. These results provide the basis for the close correlation between HB e Ag and Dane particles in the serum of persons infected with hepatitis B virus.

Mitsunobu Imai

Papers

Typing Hepatitis B Virus by Homology in Nucleotide Sequence: Comparison of Surface Antigen Subtypes

E Antigen and Anti-E in the Serum of Asymptomatic Carrier Mothers as Indicators of Positive and Negative Transmission of Hepatitis B Virus to Their Infants

Transfusion-transmitted hepatitis E caused by apparently indigenous hepatitis E virus strain in Hokkaido, Japan.

Immunochemical structure of hepatitis B e antigen in the serum.

Demonstration of Hepatitis B e Antigen in the Core of Dane Particles