Cellular Immune Responses to HBV
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Cellular Immune Responses to HBV
HBV (Hepatitis-B Virus) belongs to a family of closely related DNA viruses called the Hepadnaviruses. Included in this family are the WHV (Woodchuck Hepatitis Virus), the DHBV (Duck Hepatitis-B Virus) and several other avian and mammalian variants. All the hepadnaviruses have similar hepatotropism and life cycles in their hosts. Hepadnavirus replication is believed to be largely restricted to the liver because virus entry into hepatocytes is dependent on the presence of a receptor that is predominantly expressed on this cell type (Ref.1). The viral genome of HBV is a partially duplex circular DNA of 3.2 kb that encodes four overlapping open reading frames. The preS-S (presurface-surface) region of the genome encodes the three viral surface antigens by differential initiation of translation at each of three in-frame initiation codons. The most abundant protein is the 24-KD S protein (which is known as HBsAg). The preC-C (precore-core) region encodes HBcAg (Hepatitis-B core Antigen) and HBeAg (Hepatitis-B e Antigen). HBeAg is not required for viral replication and plays no role in viral assembly. The P coding region is specific for the viral polymerase, a multifunctional enzyme involved in DNA synthesis and RNA encapsidation. The X open reading frame encodes the viral X protein (HBx), which modulates host-cell signal transduction and can directly and indirectly affect host and viral gene expression (Ref.2).

The hosts immune attack against HBV is the cause of the liver injury, mediated by a cellular response to small epitopes of HBV proteins, especially HBcAg, presented on the surface of the hepatocyte. HBV infections occur in two stages: the proliferative phase and an integrative phase. During the proliferative phase there is the formation of complete virions and formation of the antigens. The cell surface expression of the antigens leads to activation of cytotoxic CD8+ T-Cell and hepatocyte destruction. In the integrative phase, viral DNA is taken into the host genome. HBV replicates in hepatocytes to produce HBsAg particles and virions. Both types of particle can be taken up by Antigen-Presenting Cells, which degrade the viral proteins to peptides that are then presented on the cell surface bound to MHC-I or MHC-II (Major Histocompatibility Complex) molecules. HLA Class-I-restricted CD8+ cells recognize HBV peptide fragments derived from intracellular processing and presentation on the hepatocyte surface by HLA Class-I molecules. This recognition reaction can lead to either direct lysis of the infected hepatocyte or the release of Ifn-Gamma (Interferon-Gamma) and TNF-Alpha (Tumor Necrosis Factor-Alpha), which can down-regulate viral replication in surrounding hepatocytes without direct cell killing. (Ref.3). HLA Class-I pathway involves internal processing of HBcAg peptides within hepatocytes, leading to their display on the hepatocyte surface. CD8+ cell recognition of peptides displayed in the HLA binding groove initiates apoptosis mediated by the FasL (Fas Ligand), cytokines , and perforin. HLA Class-II-restricted CD4+T-Cell recognize externally derived HBV peptide fragments derived from viral proteins presented in the antigen groove of nonhepatic Antigen-Presenting Cells, principally macrophages. The identification of viral-protein epitopes by the CD4+ cell results is an increased synthesis of cytokines , which augment T-Cell proliferation, increase the display of HLA Class-I molecules on hepatocytes, and decrease viral replication. In certain circumstances, CD4+ cells may also be capable of a cytolytic attack (Ref.3 & 4).

HBV infection is highly species specific; only humans and closely related species are known to be susceptible to HBV infection. It is transmitted by percutaneous and mucous membrane exposure to infected blood and to infected body fluids that contain blood. In most Western countries, the major routes of transmission among adults are illicit injection, drug use and sexual contact. Almost all adults newly infected with HBV develop acute hepatitis with jaundice as a predominant feature (Ref.4). Infection with HBV results in a broad spectrum of liver disease, ranging from subclinical infection to acute, self-limited hepatitis and fatal, fulminant hepatitis. Exposure to HBV, particularly when it occurs early in life, may also result in an asymptomatic carrier state that can progress to chronic active hepatitis, cirrhosis of the liver, and eventually hepatocellular carcinoma. Persistent infection with HBV represents a major health problem worldwide, with more than 350 million chronically infected patients at risk of developing liver disease. Many chronically infected individuals eventually acquire severe liver disease that may progress to hepatocellular carcinoma, one of the most common forms of human cancer. The association between HBV infection and the development of liver cancer has stimulated interest in the production of therapeutic strategies for both the prevention of HBV infection and the clearance of virus from those who are chronically infected. While the implementation of HBV vaccine programs has decreased the number of new chronic infections in some parts of the world, it has no impact on those already infected. HBV therefore continues to be a pathogen of major importance. The present therapies for individuals chronically infected with HBV include treatment with Alpha interferon, Lamivudine (3TC), or Adefovir Diprovoxil (Ref.5).