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C hair of M icrobiology, V irology, and I mmunology

C hair of M icrobiology, V irology, and I mmunology. Hepatitis Viruses. Characteristics of Human Hepatitis Viruses. Global Prevalence of Hepatitis A Infection. HAV Prevalence. High. Intermediate. Low. Very Low. HEPATITIS A VIRUS.

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C hair of M icrobiology, V irology, and I mmunology

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  1. Chair of Microbiology, Virology, and Immunology Hepatitis Viruses

  2. Characteristics of Human Hepatitis Viruses

  3. Global Prevalence of Hepatitis A Infection HAV Prevalence High Intermediate Low Very Low

  4. HEPATITIS A VIRUS

  5. Hepatitis A virus particles found in fecal extracts by immunoelectron microscopy. Both full and empty particles are present. The virus is 27 to 29 nm in diameter. (X 125,000.)

  6. Genome organisation of HAV

  7. Hepatitis A Virus Life Cycle

  8. Hepatitis A Transmission • Fecal-oral contamination of food or water Food handlers Raw shellfish Travel to endemic areas • Close personal contact Household or sexual contact Daycare centers • Blood-borne (rare) Injecting drug users For example. An epidemic of HAV that occurred in Shanghai, China, in 1988 in which 300,000 people were infected with the virus resulted from eating Anadara subcrenata obtained from a polluted river.

  9. Pathogenesis

  10. Pathogenesis of HAV • HAV replicates slowly in the liver without producing apparent cytopathological effects (CEPs). In the absence of cytolysis, the virus readily establishes a persistent infection. • Jaundice, resulting from damage to the liver • Antibody is detected and cell-mediated immune responses to the virus

  11. Hepatitis A - Clinical Features • Incubation period: Average 30 days Range 15-50 days • Jaundice by <6 yrs, <10%age group: 6-14 yrs, 40%-50% >14 yrs, 70%-80% • Complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis • Chronic sequelae: None

  12. Concentration of Hepatitis A Virusin Various Body Fluids Feces Body Fluid Serum Saliva Urine 102 104 100 106 108 1010 Infectious Doses per ml

  13. Clinical Variants of Hepatitis A Infection • Asymptomatic (anicteric) disease • Children under 6 years of age, > 90% • Children from 6-14 years old, 40-50% • Symptomatic (icteric) disease • Adults and children over 14, 70-80%

  14. Symptoms ALT Total anti-HAV Fecal HAV IgM anti-HAV 4 5 6 12 24 0 1 2 3 Months after exposure Typical Serologic Course of Acute Hepatitis A Virus Infection

  15. Hepatitis A Vaccine Efficacy Studies Vaccine Site/Age Efficacy Vaccine Group (95% CI) Ò HAVRIX Thailand 94% (SKB) 1-16 yrs (79%-99%) 2 doses 360 EL.U. ä VAQTA New York 100% (Merck) 2-16 yrs (85%-100%) 1 dose 25 units

  16. HEPATITIS B VIRUS About 300 million people world-wide are thought to be carriers of HBV, and many carriers eventually die of resultant liver disease. HBV causes acute hepatitis that can vary from a mild and self limiting form to an aggressive and destructive disease leading to postnecrotic cirrhosis. Many HBV infections are asymptomatic (especially in children).

  17. >8% 2-8% <2% Prevalence of HBsAg Carrier State WHO

  18. HEPATITIS B VIRUS

  19. Fraction of the blood scrum from a patient with a severe ease of hepatitis. The larger spherical particles, or Dane particles, are 42 nm in diameter and are the complete hepatitis B virus. Also evident are filaments of capsid protein (HBsAg).

  20. HEPATITIS B VIRUS:

  21. HOW THE VIRUSREPRODUCES ?? 1. First the virus attached to a liver cell membrane. 2. The virus is then transported into the liver cell

  22. 3. The core particle then releases it’s contents of DNA and DNA polymerase into the liver cell nucleus. 4. Once within the cell nucleus the hepatitis B DNA causes the liver cell to produce, via messenger RNA; HBs protein, HBc protein, DNA polymerase, the HBe protein, and other undetected protein and enzymes. • DNA polymerase causes the liver cell to make copies of hepatitis B DNA from messenger RNA.

  23. 5. The cell then assembles ’live’ copies of virus.

  24. 6. However because of the excess numbers of surface proteins produced many of these stick together to form small spheres and chains. These can give a characteristic “ ground glass” appearance to blood samples seen under a microscope. 7. The copies of the virus and excess surface antigen are released from the liver cell membrane into blood stream and from there can infect other liver cells.

  25. HBV: Replication • Reverse transcription:one of the mRNAs is replicated with a reverse transcriptase making the DNA that will eventually be the core of the progeny virion • RNA intermediate: HBV replicates through an RNA intermediate and produces and release antigenic decoy particles. • Integration: Some DNA integrates into host genome causing carrier state

  26. Genome of HBV virus Genome: 3.200 nucleotídes S P C X

  27. Open Reading Frames • There are 4 open reading frames derived from the same strand (the incomplete + strand) • S - the 3 polypeptides of the surface antigen (preS1, preS2 and S - produced from alternative translation start sites. • C - the core protein • P- the polymerase • X - a transactivator of viral transcription (and cellular genes?). HBx is conserved in all mammalian (but not avian) hepadnaviruses. Though not essential in transfected cells, it is required for infection in vivo.

  28. Pré S1 Pré S2 gene S gene C Pré C HBV Genome AgHBs DNA Polimerase gene P AgHBc AgHBe

  29. ANTIGEN OF HEPATITIS B VIRUS: HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr) HBcAg = inner core protein (a single serotype) HBeAg = secreted protein; function unknown

  30. In HBsAg there are some determinants, which are responsible for 10 subtypes of this antigen. “а” determinat is general. There are “d” and “y”, and two additional - “w” and “r”. So, there are four main subtypes: “adw”, “ayw”, “adr”, “ayr”. Other determinants - f, g, j, n, t, x.

  31. HBV SPREAD MAINLY BY PARENTERAL ROUTE • DIRECT PERCUTANEOUS INOCULATION OF INFECTED SERUM OR PLASMA • INDIRECTLY THROUGH CUTS OR ABRASIONS • ABSORPTION THROUGH MUCOSAL SURFACES • ABSORPTION OF OTHER INFECTIOUS SECRETIONS (SALIVA OR SEMEN DURING SEX)

  32. HBV SPREAD MAINLY BY PARENTERAL ROUTE • POSSIBLE TRANSFER VIA INANIMATE ENVIRONMENTAL SURFACES • VERTICAL TRANSMISSION SOON AFTER CHILDBIRTH (TRANSPLACENTAL TRANSFER RARE) • CLOSE, INTIMATE CONTACT WITH AN INFECTED PERSON

  33. Pathogenesis and Immunity • Virus enters hepatocytes via blood • Immune response (cytotoxic T cell) to viral antigens expressed on hepatocyte cell surface responsible for clinical syndrome • 5 % become chronic carriers (HBsAg> 6 months) • Higher rate of hepatocellular carcinoma in chronic carriers, especially those who are “e” antigen positive • Hepatitis B surface antibody likely confers lifelong immunity (IgG anti-HBs) • Hepatitis B e Ab indicates low transmissibility

  34. Determinants or acute and chronic HBV infection From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,

  35. WHO IS AT GREATEST RISK FOR HBV INFECTION? • LAB PERSONNEL WORKING WITH BLOOD PRODUCTS • SEXUALLY ACTIVE HOMOSEXUALS • PERSONS WITH MULTIPLE AND FREQUENT SEX CONTACTS • MEDICAL/DENTAL PERSONNEL DRUG ABUSERS • BLOOD PRODUCT RECIPIENTS • ACCOUNTS FOR 5-10% POSTRANSFUSION HEPATITIS • HEMODIALYSIS PATIENTS • PEOPLE FROM SOUTHEAST ASIAN COUNTRIES (70-80%)

  36. HBV • 300,000 NEW CASES IN U.S. PER YEAR • LIFETIME RISK FOR AVERAGE PERSON IS 5% • SEXUAL PROMISCUITY > RISK • LIFETIME RISK FOR DENTIST IS 13-28%

  37. Jaundice

  38. CHARACTERISTICS OF HBV INFECTION • INFECTION IS USUALLY SELF LIMITING, COMPLETE RESOLUTION IN 6 MONTHS • HOWEVER, WHEN INFECTED • 5% ADULTS CHRONIC CARRIERS • 20% CHILDREN CHRONIC CARRIERS • 80-90% NEONATES AND INFANTS BECOME CHRONIC CARRIERS

  39. Acute Infection HBV DNA HBeAg Anti-HBe Anti-HBs Anti-HBc HBsAg Anti-HBc IgM 0 2 4 6 Months Years HBV - Diagnosis

  40. HBV DNA HBeAg Anti-HBe HBsAg Anti-HBc IgG Anti-HBc IgM Months Years HBV - Diagnosis Chronic Infection

  41. PRACTICE • HBsAG N. • HBcAB (TOTAL) P. • HBsAB P. • HAV-IGM N. • HCV N. • PAST INFECTION.

  42. PRACTICE • HBsAg N. • HBcAB (total) N. • HBsAB P. • HAV-IGM N. • HCV N. • IMMUNIZATION.

  43. PRACTICE • HBsAg P. • HBcAB (Total) P. • HBsAB N. • HAV-IGM N. • HCV N. • MAY BE ACUTE OR CHRONIC. • Order Hep. B Core IgM to clarify. • The IgM will be positive , If Acute.

  44. Vaccine Age Group Dose Volume # Doses (μg) (ml) Engerix-B 0-19 yr 10 0.5 3 (mo 0,1,6)  20 yr 20 1.0 3 (mo 0,1,6) Adults on hemodialysis 40 2.0 4 (mo 0,1,2,6) Recombivax HB 0-19 yr 5 0.5 3 (mo 0,1,6)  20 yr 10 1.0 3 (mo 0,1,6) (Optional 2-dose) 11-15 yr 10 1.0 2 (mo 0, 4-6) Adults on hemodialysis 40 1.0* 3 (mo 0,1,6) HBV - Vaccine

  45. Combined HAV and HBV - Vaccine Bivalent HAV and HBV vaccine 1ml contains 720 ELISA Units of inactivated HAV and 20 ug of recombinant HBsAg protein Dosage: 1 ml at 0, 1, 6 months Recommended for all susceptible persons  18 years at risk of exposure to both HAV and HBV, including travelers to areas of high/intermediate endemicity for both viruses

  46. Therapeutic Agents Immune Modulators Nucleo(s)tide analog InterferonLamivudine Thymosin Adefovir dipivoxil Therapeutic vaccines Emtricitabine Entecavir L-dT/ L-dC Clevudine Famciclovir

  47. Characteristics of hepatitis C viruses

  48. Model of Human Hepatitis C Virus Lipid Envelope Capsid Protein Nucleic Acid Envelope Glycoprotein E2 Envelope Glycoprotein E1

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