8..hepatitis b viruses 2003
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8..hepatitis b viruses 2003

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    8..hepatitis b viruses 2003 8..hepatitis b viruses 2003 Presentation Transcript

    • Hepatitis B virus (HBV) causes Hepatitis B. It belongs to the Hepadnavirus family of DNA viruses. It has an enveloped, icosahedral nucleocapsid core containing a partially DS circular DNA genome. The incomplete strand is the plus strand and is associated with a viral DNA polymerase that functions as both a DNA dependent-DNA polymerase and RNA-dependent reverse transcriptase. This polymerase can repair the gap in the plus strand and render the genome fully double-stranded. The envelope contains a protein called Surface Antigen (HBsAg) that is important for lab diagnosis and immunization.
    • The viral genome contains 4 genes: S-gene; C-gene; P- gene and the X-gene. S-gene codes for the surface antigen. C-gene codes for the core antigen (HBcAg) and the eantigen (HBeAg). P-gene codes for the polymerase. X-gene codes for the X-protein, which is an activator of viral RNA transcription.
    • The core antigen (HBcAg) forms the nucleocapsid core of the virion and the e-antigen (HBeAg)is the transmissibility factor secreted from the infected cells into the blood. HBV is the only human virus that produces three different particles that of many spheres (22 nm) and filaments (22nm wide) along with the virions (42nm) as seen in the electron microscopy of a patients serum.
    • HBV has one serotype based on HBsAg for vaccine purposes and induction of immune response. The specificity of HBV for liver cells is due to the virus specific receptors on the hepatocyte cell membrane (facilitating their entry) and transcription factors found only in the hepatocyte that enhance viral mRNA synthesis. Human only hosts of HBV.
    •  Replication of HBV:  After entry of the virus and its uncoating, the virion DNA polymerase synthesizes the missing portion of DNA and a double stranded closed circular DNA is formed in the nucleus.  This DNA serves as a template for mRNA synthesis using the cellular RNA polymerase.  After individual mRNA’s coding for specific proteins are made, a full length transcript of the positive strand (RNA) is generated.  This full length transcript of RNA generated serves as a template for the minus strand of progeny DNA using RNA-dependent DNA polymerase or reverse transcriptase (inside the nucleus).  This minus strand of DNA now serves as a template for the plus strand of the genome DNA, using DNA polymerase.  The RNA dependent DNA synthesis takes place within the newly assembled virion core in the cytoplasm.
    • Hepadna viruses are the only viruses that produce genome DNA by reverse transcriptase with mRNA as the template. The virion polymerase plays both the roles of RNA dependent reverse transcriptase and DNA-dependent DNA polymerase. Some of the progeny DNA integrates into the host cell genome and this maintains the carrier state. Progeny HBV with its HBsAg coating envelope releases from the cell by budding through the cell membrane.
    • Transmission is via blood, during sexual intercourse and during childbirth from mother to the newborn. Only very small amounts of blood necessary for transmission as evidenced by transmission through needle-stick injuries. A high incidence of hepatocellular carcinoma associated with HBV infection indicates that HBV may well be a human tumor virus. Also immunization against HBV reduced the incidence of hepatoma in children.
    • Pathogenesis includes the virus infecting the hepatocytes after entering the blood stream and the viral antigens subsequently displayed on the surface of the cells elicit a Cytotoxic T-cell mediated immune attack resulting in inflammation and necrosis. The pathogenesis of HBV is probably due to the result of this cell-mediated immunity injury. HBV itself does not cause any CPE. It is these antigen-antibody complexes that cause some of the early symptoms such as arthralgias, arthritis and urticaria and some later complications of chronic hepatitis such as glomerulonephritis, cryoglobulinemia and vasculitis.
    • 5% of patients become chronic carriers defined as HBsAg persisting in their blood for at least 6 months. A high rate of hepatocellular carcinomas seen in chronic carriers. Please note that the HBV does not have an oncogene and as such the carcinoma appears to be the result of persistent cellular regeneration that attempts to replace the dead hepatocytes during HBV infection. It could also be due to insertional mutagenesis when the HBV genome integrates into the hepatocyte DNA. Life long immunity mediated by the humoral antibodies against the HBsAg.
    • Clinical findings: Many HBV infections are asymptomatic and detected only by the presence of anti-HBsAg. Incubation period is of 10-12 weeks and symptoms similar to Hepatitis A. However, HBV infections are more severe and lifethreatening as well. It may lead to cirrhosis and death. In cases of HBV and HIV infections together, HBV should be treated first as Immune reconstitution after HIV treatment may result in increased damage to hepatocytes due to the reconstituted Cytotoxic T-cells.
    • Lab diagnosis: Immunoassay available for detecting HBsAg. HBcAg test to detect antibodies is not readily available, especially helpful during the window phase (after the disappearance of HBsAg and the appearance of anti-HBsAg in the blood). HBeAg indicates a high likelihood of transmissibility.
    • Treatment: Typically no anti-viral therapy is used in acute hepatitis B. In chronic cases, a combination of peginterferon alfa-2a or perinterferon alfa-2b along with/or a nucleoside analogue such as Lamivudine, Adefovir, Entecavir or telbivudine that inhibits the reverse transcriptase of HBV. A combination of tenofovir and emtricitabine can also be used. Nucleoside analogues are better tolerated than peginterferons. These drugs reduce hepatic inflammation and lower the viral load in chronic state and do not cure the infection. Replication starts once the drug is stopped.
    • Prevention by a recombinant vaccine of HBsAg produced in yeasts. Highly effective in prevention. Hepatitis B immune globulin (HBIG) containing a high titer of anti-HBsAg for individuals exposed to HBsAg blood. All blood for transfusion to be screened for HBsAg.