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Lecture 29 Hepatitis Viruses

Lecture 29 Hepatitis Viruses. Hepatitis:. Inflammation of the liver. Causes : Toxic (alcoholic), Infectious (parasites, fungi, bacterial, viral) and Autoimmune. . Types :. Self-limited hepatitis : short duration, no carrier state.

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Lecture 29 Hepatitis Viruses

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  1. Lecture 29 Hepatitis Viruses

  2. Hepatitis: Inflammation of the liver Causes: Toxic (alcoholic), Infectious (parasites, fungi, bacterial, viral) and Autoimmune. Types: Self-limited hepatitis: short duration, no carrier state Chronic persistent hepatitis: virus persists without symptoms Chronic active hepatitis: virus persists and causes necrosis, fibrosis leading to cirrhosis and liver failure. May have periods without symptoms. Symptoms include jaundice, anorexia, flu-like, vomiting, nausea, colitis and autoimmune disease.

  3. Progression of Liver Disease Fibrosis: After becoming inflamed, the liver repairs itself and scarring occurs. Cirrhosis: Scars begin to join together, nodules may form, blood flow is blocked. The liver shrinks and becomes hard. Liver failure: Severe cirrhosis, liver is unable to filter wastes, toxins and drugs from the blood. Does not produce clotting factors. Healthy liver Viral hepatitis

  4. Liver Largest internal organ 4 Functions 1. Purification…………removes drugs/toxins/ alcohol 2. Synthesis…………..protein metabolism, serum proteins, bile, clotting factors 3. Storage……………..mineral, vitamins, sugars 4. Transformation…….converts hormones into active forms

  5. Viral Hepatitis – Overview Type of Hepatitis A B C D E Source and transmission fecal-oral Blood sexual Blood sexual Blood sexual fecal-oral no yes yes yes no Chronic infection Prevention immunization immunization blood donor immunization; ensure safe screening; drinking water risk behavior risk behavior risk behavior modification modification modification

  6. Hepatitis A Virus

  7. HAV Overview Small RNA virus Non-enveloped Picornavirus family Pico (greek very small) RNA virus (Polio, Rhinovirus) Single serotype Acute or asymptomatic Protective antibody confers lifelong immunity       Acid stable Acquired from contaminated water, shellfish, salad   22,700 cases in US per year, <0.4% cases are fatal 

  8. Symptoms of HAV  Children <6 years of age usually are asymptomatic (70%) Usually (30%) anicteric (no jaundice) After an incubation period of 28 days……nonspecific illness fever, malaise, anorexia, Followed by gastrointestinal symptoms…nausea, abdominal discomfort, dark urine and jaundice (70-80%) Course of illness usually <2 months 15-20% of patients relapse lasting up to 6 months Acute liver failure is rare (0.015-0.5%)….usually young children and older adults      

  9. CONCENTRATION OF HEPATITIS A VIRUSIN VARIOUS BODY FLUIDS

  10. GEOGRAPHIC DISTRIBUTION OF HEPATITIS A VIRUS INFECTION

  11. Hepatitis A particles consist of one RNA molecule surrounded by capsid proteins Genomic RNA is infectious (1 million times less infectious than particles)

  12. The HAV Genome VPg protease Capsid proteins polymerase The structural and non-structural proteins and the highly structured 5´ and 3´ UTRs are represented.

  13. HAV Life Cycle

  14. HAV Life Cycle The HAV life cycle. (a) The virus enters the hepatocyte via an interaction with a cellular receptor. (b) This is followed by uncoating of the viral particle and release of the positive-sense RNA genome into the cell. (c) An internal ribosome entry site within the 5 nontranslated segment of the genome mediates cap-independent translation of the viral polyprotein. (d) The polyprotein undergoes co- and post-translational proteolytic processing directed by the viral protease, 3C. (e) Nonstructural viral proteins assemble and commence synthesis of a negative-strand copy of the viral genome. (f) The negative-strand copy of the genome is used as template for synthesis of multiple new copies of genomic positive-strand RNA. (g) Some of this newly synthesized positive-sense RNA is recycled for further RNA synthesis or translation. (h) Other positive-strand RNA molecules are packaged into new viral particles formed by assembly of the structural proteins. (i) Newly assembled HAV particles are secreted by the cell across the apical membrane of the hepatocyte into the bile duct, from which they are passed into the bile and small intestine.

  15. HAV: Treatment and Vaccine Treatment 99% of patients recover without treatment. Rest and proper nutrition results in recovery at 2 months. Vaccine Cell culture-adapted virus grown in human fibroblasts. Purified product inactivated with formalin.

  16. Hepatitis B Virus

  17. HBV Overview  Enveloped virus Double-stranded DNA virus Family: Hepadnaviridae Hepa*DNA*virus   350 million chronic carriers in the world (250 million in Asia Pacific) In U.S. 1.2 million carriers, 5,500 deaths per year   Eight genotypes of HBV, designated genotypes a-h 

  18. Symptoms of HBV One third of world population has been infected with HBV   One third of patients have “silent” disease  Acute, recovery with immunity…………….90%  Acute case fatality rate………………………1%  Chronic liver disease……………………….10% → 25% cirrhosis + liver cancer  Symptoms include: fever, headache, muscle aches, fatigue, loss of appetite, nausea, vomiting and diarrhea, dark urine, abdominal pain, jaundice.

  19. Core 3.2 Kb DNA polymerase Surface

  20. 1. Replication occurs in the nucleus 2. Genomic integration can occur 3. Reverse transcriptase (RNA to DNA) done in particles in cytoplasm

  21. HBV Genome

  22. HBV Genome dsDNA

  23. HBV Genome dsDNA RNA

  24. HBV Genome Surface Antigen dsDNA Polymerase (RNA → DNA) Core RNA Oncogene?

  25. HBV surface antigen (HBsAg) is produced in vast excess

  26. HBV: Treatment and Vaccine Treatment 30-40% of patients recover with interferon. Other antivirals such as nucleoside analogues are used. Vaccine Licensed in 1982. Purified surface antigen made in yeast cells form natural-like particles.

  27. Hepatitis Delta Virus

  28. HDV Overview First isolated from liver biopsy from patients in Italy that had a more severe form of HBV. Is a satellite virus of HBV. Uses HBV surface antigen for packaging and requires HBV (helper virus). HDV transmission similar to HBV (blood, sexual contact). Small RNA virus or viroid encoding one protein (delta antigen). Viroid: smallest known autonomously replicating molecules, single-stranded -closed circular RNA.      

  29. Superinfection vs Coinfection Super-infection: HBV then HDV 70%-80% chronic liver disease, HBV alone = 30% Co-infection: HBV + HDV more severe acute disease than HBV alone

  30. HDV Particles

  31. HDV Genome 1679 nt RNA Genomic RNA >50% cytoplasm Antigenome nucleus Problem…………..what is the host RNA polymerase? No known human RDRP(?)…………….some evidence for RNA pol II

  32. Two forms of the delta antigen

  33. Large delta antigen is made by RNA editing     Genomic Genomic * * U C   RNA Editing   Antigenomic Antigenomic * * A G * * mRNA AUG AGG mRNA Stop codon Read through translation Small delta Ag is made Large Delta Ag is made

  34. Two forms of the delta antigen Delta antigen -Small (dAg-S): replication Delta antigen -Large (dAg-L): inhibits replication, required for virus assembly (packaging) created by RNA editing of the mRNA, which creates read through translation (19 aa longer)

  35. HDV: Treatment and Vaccine Treatment Interferon alpha, liver transplant. Vaccine HBV vaccine.

  36. Hepatitis C Virus

  37. HCV Overview  RNA virus Family: Flaviviridae (other examples include: yellow fever, West Nile, Dengue) 9.5 Kb RNA Formerly called non-A, non-B Hepatitis Incubation period 10-70 days 2% of the world population is now infected     

  38. Most HCV infections become persistent……. Acute illness <20% Chronic infection 70-85% Cirrhosis 10-20% Hepatocellular Carcinoma 1- 4% Lead reason for liver transplant     

  39. Factors Promoting HCV Infection or Severity Increased alcohol intake Age > 40 years at time of infection HBV or HIV co-infection Male gender    

  40. Hepatitis C Virus Infection United States New infections per year 26,000  Chronically infected Americans 3.2 million  Deaths from acute liver failure rare  Deaths from chronic disease 10,000/year 

  41. Sources of Infection forPersons with Hepatitis C Sexual 15% Injecting drug use 60% Transfusion 10% (before screening) Occupational 4% Other 1% Unknown 10% Source: Centers for Disease Control and Prevention

  42. New Cases of Hepatitis C Virus 140 120 100 80 New Infections/100,000 60 40 20 Decline in transfusion recipients 1960 1970 1980 1990 2000

  43. HCV Genome Structural Proteins Nonstructural Proteins NS4A Core E1 E2 NS2 NS3 NS4B NS5A NS5B p7 nucleo- capsid Ca++ ? IFN polymerase envelope viral proteases and cofactor IFN

  44. Current problems with HCV: Chimp only animal model No vaccine Only effective treatment is interferon or interferon+ribavirin

  45. Genotype-specific IFN Response Sustained Response Rate + Ribavirin Genotype 1 10-12% 40% 2 50% 70% 3 53% 70%

  46. HCV: Treatment and Vaccine Treatment Interferon or combination Interferon plus ribavirin. Vaccine None.

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