• Home
• Animations
• Chapter Outlines
• Animated Flashcards
• Interactive Glossary
• Crossword Puzzles
• Research and
  Reference Links
• Virology in the News
• Instructors:
  Click here for more information about this text.

Chapter Outlines

Chapter 17      Hepatitis Viruses

[View Chapter Outlines list]

17.1 The History of Viral Hepatitis Hepatitis - inflammation of the liver Classic symptom-jaundice Caused by a number of viruses and sometimes alcohol or prescription drugs Hepatitis epidemics in history War -crowding and unsanitary conditions of military encampments created an ideal environment for hepatitis A viruses to be transmitted Camp jaundice and outbreaks recorded: Napoleonic Wars U.S. Civil War - camp jaundice WWI -trench warfare WWII - serum hepatitis (via vaccination) and infectious hepatitis (contaminated battle fields) Hepatitis C and U.S. Military Veterans Today 8-9% of Veteran Affairs (VA) medical center patients are positive for hepatitis C antibodies Vietnam era of hepatitis epidemics Combats survived multiple blood transfusions Intravenous heroin use Sharing of razors and other nonsterile instruments History of tattooing History of prostitution Blood/bodily fluid exposure to healthcare and combat personnel Receipt of contaminated immune globulin for hepatitis A prior to hepatitis C screening 17.2 Epidemiology Yellow Fever virus, herpes simplex viruses, cytomegaloviruses and Epstein Barr virus can cause hepatitis. A group of unrelated pathogens termed "hepatitis viruses" cause the vast majority of virally induced hepatitis cases. The focus of this chapter is on the "hepatitis viruses" Hepatitis Viruses Each starts with a letter with the exception of the newly identified transfusion transmission virus (TTV) and SEN viruses. Hepatitis A Hepatitis B Hepatitis non-A, non-B viruses Hepatitis C Hepatitis D Hepatitis E Hepatitis G Human Hepatitis Viruses: Nomenclature and Characteristics. See Figure 17-1. Transmission of Human Hepatitis Viruses. See Table 17-1. 17.3 Clinical Features: Hepatitis A Most outbreaks associated with contaminated food or water supplies. Shellfish may become contaminated with sewage and may concentrate and retain viruses. Major mode of transmission is fecal-oral. Average incubation period is 30 days. Adults experience signs and symptoms more often than children. Onset Symptoms of HAV Fatigue Abdominal pain Loss of appetite Nausea and vomiting Dark urine Jaundice (occurs in 70-80% of individuals older than 14 years of age, less likely to occur in children) Jaundice Yellow color in the skin, mucous membranes, or eyes. Occurs when liver is not functioning properly. Yellow pigment is from bilirubin, a byproduct of old red blood cells. Hepatitis B Relatively rare in developed countries. Endemic areas - major model of spread is mother (carrier) to infant (blood of infected mother enters fetus). Other high-risk groups IV drug users Hemodialysis patients Persons with multiple sex partners Institutionalized patients Healthcare workers Average incubation period is 80 days. 30% of individuals have no signs and symptoms If symptoms occur, they are similar to hepatitis A + joint pain. Chronic hepatitis B infections occurs in 5-10% of cases. Chronic infections lead to: Cirrhosis of liver Hepatocellular carcinoma (HCC) or liver cancer HCC HBV DNA sequences are found in HCC tumor DNA. Integration of HBV DNA occurs in breaks in the cellular DNA of hepatocytes(liver cells). Chronic HBV infections cause ongoing inflammatory responses and oxidative damage to chromosomal DNA of hepatocytes. Death from chronic liver disease results in 15-25% of individuals. Hepatitis C Prior to 1989: cases of hepatitis of unknown etiology (hepatitis A and B viruses ruled out) These cases were referred to be caused be "hepatitis non-A, non-B" viruses. 1989 - scientists found a new viral genome present in hepatocytes Eventually the new viral pathogen was identified, visualized by TEM etc. Hepatitis C (HCV): Major Public Health Problem Many infected people show few or no signs of disease for years and even decades ("silent epidemic"). HCV infection common in the developed world. ~1.8% of U.S. population is infected with HCV. HCV Prevalence in the U.S. See Figure 17-4. HCV Transmission Incubation period is 6-7 weeks. Spread almost exclusively through blood contact. Individuals who received blood products before 1992 are at risk for contracting HCV. Donated blood screening for HCV did not begin until 1992. If signs or symptoms are present, they are similar to other hepatitis infections. Between 55-85% of infected persons experience a chronic infection, resulting in chronic liver disease. Chronic infection can lead to cirrhosis of the liver and HCC in 5-20% of infected persons (See Chapter 10). Hepatitis D (HDV) HDV requires the presence of HBV to replicate. Symptoms of HDV are indistinguishable from HBV infection. Highest risk factor for HDV infection in the Western World is intravenous drug use. 17-90% of IV drug addicts test positive for HDV Hepatitis E (HEV) HEV is endemic in the developing countries of Asia and Africa HEV rare in industrialized nations. Sporadic cases reported in the U.S., France, Italy and England. Mode of transmission - similar to HAV (fecal-oral route) Person to person transmission rare Incubation period - 40 days (ave) Outbreaks often associated with fecally contaminated water supplies. HEV Causes a More Severe Illness than HAV HEV causes 1-3% mortality (general population) HEV causes 15-25% mortality in pregnant women Some evidence that hepatitis E may be a zoonotic disease (from pigs) HEV isolates are genetically similar to pig HEV strains isolated from pigs in the U.S. Hepatitis Non-A-E Agents Hepatitis G (HGV) SEN Transfusion Transmission Virus or Torque Teno Virus (TTV) 17.4 Laboratory Diagnosis of Viral Hepatitis Infections Diagnosis based on: Symptoms Blood tests for liver enzymes Viral antibodies (e.g. IgM) Viral genetic material (e.g. RT-PCR or PCR) Blood Samples are Tested for Two Liver Enzymes Aspartate aminotransferase (AST) Alanine aminotransferase These enzymes are normally found in the liver but spill into the blood if the liver is damaged, thus raising the enzyme levels in the blood. Nucleic acid tests (PCR, RT-PCR) to detect viral genomes are only available in specialized laboratories. Patients with chronic hepatitis are harder to diagnose because these patients do not have nausea or jaundice until the liver damage is very advanced. Serology (detection of IgM antibodies) is used to detect HAV, HBV and HCV). Natural History of Hepatitis B and C Infections. See Figure 17-6 17.5 Screening the Blood Supply for Viral Hepatitis Agents American Red Cross began screening for: 1971 Hepatitis B surface antigen 1987 anti-HBcAg 1986-2003 screening for elevated alanine aminotransferase levels 1990 anti-HCV 1999 nucleic acid test for HCV genomes Blood is not screened for other hepatitis viruses. U.S. blood supply is one of the safest in the world. 17.6 Pathogenesis: Chronic Hepatitis Chronic hepatitis Inflammation of liver is active Persists for more than 6 months Increased alanine aminotransferase in serum Hepatitis B, C, D and G viruses cause chronic hepatitis infections Chronic liver damage may results in cirrhosis Formation of fibrous tissues, nodules, scarring that interferes with liver function and blood circulation Late complication of chronic hepatitis is HCC 17.7 Hepatitis Virus Life Cycles Hepatitis viruses belong to 5 different families. Two of the hepatitis viruses are unassigned. Five of the eight viruses (hepatitis viruses A-E) have been well characterized. Virus Structure: Hepatitis A-E Spherical shaped and icosahedral symmetry 28-50 nm in diameter Enveloped (B, C, D) or nonenveloped (A or E) Hepatitis A viruses are acid and bile resistant Virus Replication Hepatitis viruses enter the bloodstream Carried to the liver Infect the hepatocytes As hepatocytes are damaged, liver cirrhosis and liver function impaired Hepatitis A Very stable in the environment Naked picornavirus +ssRNA genome that is 7.5 kb in length Viral genome and poly (A) tail at the 3' terminus of the genome 5' end of the genome contains nontranslated region of hairpins and pseudoknots. Hairpin structures act as internal ribosomal entry sites (IRES) that is necessary for cap-independent translation of the viral mRNA HAV mRNA Translation /ul> The +ssRNA viral genome acts directly as a mRNA for the synthesis of a large polyprotein. Similar to polioviruses (Chapter 11) The polyprotein is processed by a viral 3C protease into structural and nonstructural proteins of the virus. HAV Genome Replication and Particle Assembly A viral RNA dependent RNA polymerase encoded by the 3D gene synthesizes new -ssRNA intermediates used to create progeny genomic +ssRNAs Newly assemble particles are transported to the surface of hepatocytes and exported. Hepatitis B Virus Initial characterization of hepatitis B infections Baruch Blumberg collected blood samples from hemophiliacs 1963: antibodies in the serum of a New York hemophiliac reacted with an antigen present in the blood of an Australian aborigine infected with hepatitis Australia antigen was the hepatitis B surface antigen (HBsAg) Further experiments by David Dane led to the discovery of the Dane particle (complete infectious hepatitis B virus) 3 Types of Hepatitis B Particles Present During Infection Most abundant HBV particle in carriers a spherical 17-25 nm particle. Less numerous are noninfectious filamentous particles that are up to 200 nm in length Dane particles (infectious) 42 nm in diameter, enveloped. Dane particle contains the viral DNA polymerase (RT), protein kinase C, heat shock 90 protein associated with the viral genome. HBV Genome Circular partially dsDNA Full length strand is 3.2 kb Shorter strand is 1.7 kb in length Uses a replication strategy common to retroviruses HBV Attachment and Entry Host receptor is unknown Potential receptors Transferrin receptor Human liver endonexin Asialoglycoprotein receptor molecule Hepatitis B grows poorly in cell culture - difficult to study molecular mechanisms of viral attachment and entry After fusion and entry--uncoating step Uncoating/Genome Replication During uncoating, viral cores are released into the cytoplasm. Genome uncoats and enters the nucleus through the nuclear pores Host enzymes ligate the ends of the genome DNA synthesis is completed, gaps are repaired in both DNA strands Genome is now a closed circular plasmid-like dsDNA molecule called an episome The episome replicates independently of the host chromosome. HBV DNA does not integrate into the host chromosome (not integrase activity) More on the HBV Episome Acts as a template for Viral pregenomic RNA transcripts Genomic RNA transcripts transcribed by the host's RNA polymerase II HBV genome 4 promoters 2 enhancers Overlapping ORFs translated into 7 proteins (Table 17-4) Several binding sites on genome recognized by transcription factors HBV RT Activity Full length, pregenomic +ssRNA is synthesized and complexed with the viral RT and protein kinase C into core particles Heat shock proteins associate with RT, allowing it to form into an active conformation Active viral RT converts the pregenomic RNA into DNA inside the particles Unlike retroviruses, HBV RT occurs by protein-priming as opposed to RNA priming Precise replication only occurs inside of intact nucleocapsids HBV Assembly and Release Nucleocapsid cores reach the ER At the ER, the nucleocapsids associate with viral surface glycoproteins and bud into the lumen of the ER/and or Golgi Empty envelopes containing viral surface proteins of the cell are continually shed, along with mature particles Coinfection of HBV and HDV HDV is a defective virus Requires the presence of a "helper" HBV to replicate The surface or outer coat of HDV consists of HBsAgs HDV associated with chronic hepatitis HDV probably uses the same cellular receptor as HBV HDV Genome Genome is 1.7 kb RNA in length (similar to a viroid) Codes for two different types of the same protein (the delta antigen; 195 or 214 amino acids) 195 AA delta protein required for HDV RNA replication 214 AA delta protein suppresses hepatitis D virus RNA replication and assembly and export of virion particles 70 molecules of delta antigen surround the viral genome HDV Genome Replication RNA genome has intramolecular basepairing During uncoating, the viral envelop is removed inside of an infected cell and is targeted to the nucleus The cellular RNA polymerase II and other host factors replicate the viral genome The HDV genome is a ribozyme Genome replication occurs via a rolling circle mechanism similar to that of viroids (Chapter 19) Hepatitis C Virus (HCV) Icosahedron-shaped, enveloped virus +ssRNA flavivirus Not much information known about HCVs ultrastructure The only flavivirus that is not transmitted by arthropods Similar to picornaviruses (except HCV particles are enveloped) Viral nucleic acid cloned in 1989 HCV Genome 9.2 kb in length Contains an IRES 1 long ORF that encodes a polyprotein precursor which is cleaved into nonstructural and structural proteins by cellular and viral proteases Viral genome is translated by host ribosomes NS5b gene encodes its own RNA dependent RNA polymerase Viral entry receptors: clathrin, CD81, SR-B1 IFN resistance correlated with the HCV E1 and E2 proteins Hepatitis E Genome (HEV) +ssRNA genome Clinically indistinguishable from HAV infection HEV particles less stable than HAV Nonenveloped, icosahedral-shaped 32-34 nm in diameter 7.2 kb genome (contains short 5' and 3' noncoding regions) 3' end contains a poly(A) tail HEV Genome Lack of molecular biology information available No suitable cell culture system to propagate HEV 3 overlapping ORFs Methyltransferase Protease RNA helicase Replicase (RNA dependent RNA polymerase) Small phosphoprotein 17.8 A Quick Note about the Pathophysiology of Chronic Hepatitis Virus Infections There are enveloped and nonenveloped hepatitis viruses The enveloped viruses (HBV, HCV, HDV, HGV) cause persistent and chronic infections These viruses possess immune evasion strategies Liver damage caused by HBV and HCV may result from an autoimmune reaction directed against hepatocyte antigens initiated by viral infection 17.9 Genetic Diversity Among the Hepatitis Viruses 1 serotype of HAV, but at least 7 different types genotypes of HAV Immune globin and vaccine prepared protect travelers from HAV infection irrespective of their destination 4 major genotypes of HEV Many variants of HBV and HCV .... Viral polymerases lack proofreading ability 17.10 Management and Prevention of Hepatitis A-E Viruses Hepatitis A management No specific treatment Supportive care Prevention: handwashing and proper sanitary disposal of human feces. Passive immunity (immune globin) HAV vaccine: formalin-inactivated, cell culture produced whole-vaccines Havrix Vaqta Avaxim HBV Management and Prevention 3 licensed drugs to treat HBV Interferon a-2b (Intron A) Lamivudine Adefovir dipivoxil Immune globulin used as an adjunct to HBV vaccine in preventing HBV transmission from an infected mother to fetus HBV Vaccines Early vaccines prepared by harvesting 17-25 nm particles from plasma of chronically infected individuals Particles purified and inactivated by heat, formaldehyde, urea or pepsin. Subsequently, vaccine manufacturers used genetic engineering to express HBsAg in yeast Purified HBsAg self assembles into spherical particles resembling 17-25 nm particles found in the serum of people with chronic hepatitis HBV Vaccine Recommendations by the CDC Newborns should receive a birth dose before leaving the hospital Children age 19 and under should receive the HBV vaccine series. HBV vaccine is the first vaccine to prevent a cancer! 1990-2002 incidence of hepatitis B-related liver cancer decreased 67% HCV Management 85% of HCV infections progress to chronic liver disease No vaccine available Therapies to manage HCV infection: Pegylated interferon a-2a or pegylated a-2b and/or Ribavirin Response to therapy is measured by levels of serum transaminases and detection of HCV RNA Ribavirin + pegylated interferon a-2b over 6-12 months has increased the cure rates to 35-40% Ribavirin is teratogenic Six main genotypes of HCV Certain genotypes respond better to treatment than others HDV and HEV Management HDV infections maintained by reducing HBV replication No immune globulin or HDV vaccine HEV infections usually self-limiting Treatment is supportive No immune globulin or HEV vaccine available