Characteristics of the hepatitis B virus and pathogenesis of infection

INTRODUCTION — Hepatitis B virus (HBV) infection is a global public health problem. The spectrum of clinical manifestations of HBV infection varies in both acute and chronic disease. During the acute phase, manifestations range from subclinical hepatitis to anicteric hepatitis, icteric hepatitis, and fulminant hepatitis; during the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The clinical outcome of HBV infection depends upon the age at infection, the level of HBV replication, and the immune status of the host. (See "Hepatitis B virus: Clinical manifestations and natural history".)

This topic review will discuss the characteristics of the hepatitis B virus and the pathogenesis of HBV-related liver disease. The immune response to HBV contributes to the hepatic injury, helps control the infection, and provides the means for establishing the serologic diagnosis of HBV infection. (See "Hepatitis B virus: Screening and diagnosis in adults".)

CHARACTERISTICS OF THE VIRUS — Hepatitis B virus belongs to the family of hepadnaviruses, which include duck hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus. The complete virion or Dane particle is 42 nm in diameter. It consists of:

●An envelope composed of viral-encoded proteins and host-derived lipid components

●A core particle made up of the nucleocapsid protein, the viral genome, and the polymerase protein

HBV also produces 22 nm subviral particles in the form of filaments and spheres that are composed of envelope proteins only. These subviral particles do not contain the HBV genome and are therefore noninfectious [1].

The genome of HBV is a relaxed circular, partially double stranded DNA of approximately 3200 base pairs in length [1]. There are four partially overlapping open reading frames (ORFs) encoding the envelope (pre-S/S), core (precore/core), polymerase, and X proteins [1].

The pre-S/S ORF consists of three in-phase start codons and a common stop codon that divides the gene into pre-S1, pre-S2, and S regions encoding the large (L), middle (M), and small (S) envelope proteins, respectively (figure 1). The M and S envelope proteins are found in all forms of viral and subviral particles while the L envelope proteins are predominantly found in complete virions.

The precore/core ORF consists of two in-phase start codons (figure 2). Translation from the precore start codon produces a precore polypeptide which is post-translationally modified into a soluble protein, the hepatitis B e antigen (HBeAg). Translation from the second start codon produces the core protein (HBcAg).

The polymerase ORF overlaps with the core, envelope, and X ORFs. The polymerase protein consists of a protein primer, a spacer, a reverse transcriptase/DNA polymerase, and an RNAase H domain.

The X protein is a potent transcriptional transactivator of many promoters including HBV and cellular oncogenes. The HBx protein has been implicated in hepatocarcinogenesis. Studies also suggest that HBx plays a role in modulating transcriptional activity of covalently closed circular (ccc) DNA, and may be a target for antiviral therapy [2].

Two major transcripts (3.5 and 2.1 kb) are made [1]. The 3.5 kb RNA has heterogeneous 5'-ends:

●The precore mRNA is slightly longer and is initiated upstream of the precore start codon. It is translated into the precore polypeptide, which is then processed at both the N and C terminal ends to a smaller protein, the HBeAg (figure 2).

●The pregenomic RNA is initiated within the precore region. It serves as a replicative intermediate and is reverse transcribed into HBV DNA (figure 2). In addition, it functions as a messenger RNA for translation into the nucleocapsid and polymerase proteins.

The 2.1 kb RNA is initiated within the pre-S1 region and is translated into middle and small S proteins (figure 1). There are also at least two minor transcripts: the 2.4 kb RNA, which is translated into the large S protein (figure 1), and a smaller RNA, which is translated into the X protein.

Genotypes — HBV has been classified into 10 genotypes (A to J) based upon an intergroup divergence of 8 percent or more in the complete nucleotide sequence. HBV genotypes have been associated with a risk of hepatocellular carcinoma (HCC) development and a response to interferon therapy. (See "Clinical significance of hepatitis B virus genotypes".)

Replication cycle — The replication cycle of HBV begins with attachment of the virion to the hepatocyte membrane (figure 3) [1]. The receptor for HBV (and hepatitis D virus) has been identified as a bile salt transporter, sodium taurocholate cotransporting polypeptide (NTCP), which binds to the pre-S1 region of the HBV envelope [3]. The virion is uncoated in the hepatocyte cytoplasm and the viral genome enters the hepatocyte nucleus.

Inside the hepatocyte nucleus, synthesis of the plus strand HBV DNA is completed and the viral genome is converted into a ccc DNA.

The HBV genome replicates by reverse transcription via an RNA intermediate, the pregenomic RNA. The pregenomic RNA, nucleocapsid, and polymerase proteins are encapsidated in the virus core particle inside which reverse transcription takes place. The pregenomic RNA is the only RNA transcript which is encapsidated. Encapsidation is regulated by the pregenome encapsidation sequence (e) which is located in the precore and proximal core region.

A new minus strand HBV DNA is produced followed by the synthesis of a new plus strand HBV DNA. Nucleocapsids with the partially double stranded HBV DNA can re-enter the hepatocyte nucleus to produce more ccc DNA or be secreted as complete virions after coating with envelope proteins. The ccc DNA appears to have a long half-life and is not inhibited by approved nucleos(t)ide analogue therapies, accounting for the difficulty in achieving virus clearance during treatment of chronic hepatitis B; however, more recent studies suggest that the half-life of ccc DNA might be weeks or months and not years, raising hopes that new therapies may be able to eliminate ccc DNA [4].

PATHOGENESIS OF INFECTION — The pathogenesis of HBV-related liver disease is largely due to immune-mediated mechanisms. In some circumstances, HBV can also cause direct cytotoxic liver injury.

Immune-mediated liver injury — Both innate and adaptive immune responses contribute to immune control of HBV infection, although the T cell response is a double-edge sword playing a role in both immune control as well as liver injury [2,5-8]. HBV-related liver disease is generally thought to be related to cytotoxic T cell-mediated lysis of infected hepatocytes. However, the noncytolytic T cell immune response is also important. The following observations are consistent with this hypothesis:

●Events associated with immune clearance, such as spontaneous or interferon-induced, the hepatitis B e antigen (HBeAg) seroconversion, are often accompanied by exacerbations of liver disease as evidenced by an elevated serum ALT [9,10].

●Patients with chronic hepatitis B who clear HBeAg have more vigorous cytotoxic T lymphocyte responses to HBV antigens than those who remain HBeAg positive [11]. However, in HBeAg-positive patients the T cell response to HBV among those in the immune tolerance phase is not necessarily weaker than the T cell response among those in the immune active phase. Thus, the difference between these two phases is mainly in the inflammatory response and not the T cell response [12]. (See "Hepatitis B virus: Clinical manifestations and natural history", section on 'Phases of chronic HBV infection'.)

●Fulminant hepatitis B is believed to be due to massive immune-mediated lysis of infected hepatocytes. This explains why many patients with fulminant hepatitis B have no evidence of HBV replication at presentation.

In addition to promoting hepatic injury, both the T cell and antibody responses to HBV help to control the infection (see "Hepatitis B virus: Screening and diagnosis in adults"). In one study, for example, HBV-specific cytotoxic T cells from patients studied up to 23 years after clinical and serologic recovery expressed activation markers indicating recent contact with HBV antigens [13]. This observation suggests that complete eradication of HBV rarely occurs after recovery from acute hepatitis and that traces of virus can maintain the T and B cell responses for decades following clinical recovery, which in turn keep the virus under control and maintain high levels of hepatitis B surface antibody (anti-HBs) [13,14].

In a study of five patients who were identified during the incubation phase of acute HBV infection, NK cell activation was detected first followed by HBV-specific T cell response [15]. The presence of HBV-specific CD8+ and CD4+ cells during the incubation phase suggests that these cells play an important role in the control of infection and in the initiation of events that lead to liver damage. Maximal reduction in HBV-DNA levels occurred prior to peak increase in serum ALT levels, suggesting that viral control is mediated through noncytolytic as well as cytolytic mechanisms.

Direct cytotoxic liver injury — HBV is generally not a cytopathic virus. In most patients with chronic hepatitis B, for example, there is no direct correlation between viral load and the severity of liver disease. This is particularly true during the early phase of perinatally acquired HBV infection in which there is high serum HBV DNA but normal serum ALT concentrations [16]. Nevertheless, direct cytopathic liver injury can occur when the viral load is very high as in fibrosing cholestatic hepatitis, an unusual form of liver disease seen in some patients with recurrent hepatitis B following liver transplantation [17]. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)

Role of viral variants — Mutations in all regions of HBV have been found in patients with chronic HBV infection. Some of these mutations, such as the precore stop codon mutation, have been incriminated in causing more severe liver disease (figure 2) [18-20]. However, these variants have also been found in asymptomatic carriers [21], suggesting that the mutations alone are not necessarily pathogenic. Nevertheless, HBV mutations can potentially modulate the severity of liver disease by altering the level of HBV replication or the expression of immunogenic epitopes. Some variants, for example, do not make HBeAg. Nevertheless, the virus can continue to replicate (as determined by the presence of HBV DNA in serum and elevated serum ALT) [22,23] and, in the case of four surgeons, transmit the infection to others [24]. (See "Clinical significance and molecular characteristics of common hepatitis B virus variants".)

Development of chronic infection — Patients who progress to chronic HBV infection have weak and limited immune response to HBV epitopes [11,25-28]. Some studies also found relatively increased activation of the host's immunosuppressive mechanisms [29].

SUMMARY AND RECOMMENDATIONS

●The genome of hepatitis B virus (HBV) is a relaxed circular, partially double stranded DNA of approximately 3200 base pairs in length, and the virion is 42 nm in diameter. HBV belongs to the family of hepadnaviruses, which include the duck hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus. (See 'Characteristics of the virus' above.)

●HBV has been classified into 10 genotypes (A to J) based upon an intergroup divergence of 8 percent or more in the complete nucleotide sequence. HBV genotypes may influence hepatocellular carcinoma risk and response to interferon therapy. (See 'Genotypes' above and "Clinical significance of hepatitis B virus genotypes".)

●The pathogenesis of HBV-related liver disease is largely due to immune-mediated mechanisms. In some circumstances, HBV can cause direct cytotoxic liver injury. (See 'Pathogenesis of infection' above.)